
Glass. 



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COPYRIGHT DEPOSIT 



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PHARMACOLOGY 

LINICAL AND EXPERIMENTAL 



A GROUNDWORK OF MEDICAL 
TREATMENT, BEING A TEXT-BOOK 
FOR STUDENTS AND PHYSICIANS 

BY 

DR. HANS H. MEYER, of Vienna 

AND 

DR. R. GOTTLIEB, of Heidelberg 

PROFESSORS OF PHARMACOLOGY 

AUTHORIZED TRANSLATION INTO ENGLISH BY 
JOHN TAYLOR HALSEY, M.D., 

PROFESSOR OF PHARMACOLOGY, THERAPEUTICS, AND CLINICAL MEDICINE, TULANE UNIVERSITY 

WITH 65 TEXT ILLUSTRATIONS, 7 IN COLOR 




PHILADELPHIA & LONDON 
J. B. LIPPINCOTT COMPANY 






COPVRIGH7, r5>14 
BY J. B. LJPPINCOTT COMPANTT 



APR 21 1914 



Electrotyped and Printed by J. B. Lippincolt Company 
The Washington Square Press, Philadelphia, U. S. A. 



'CI.A369784 



AUTHORS' PREFACE 

Experimental pharmacology in its widest significance deals with 
the reaction of living organisms to various chemical agents or, otherwise 
expressed, with their behavior under chemically altered conditions of 
life. Consequently pharmacology is to be looked upon simply as one 
portion of biology. 

Among the endless number of possible pharmacological reactions, 
those possess a special interest, the study of which should aid the 
physician in practicing his healing art. This portion of pharmacology, 
"scientific drug therapy" in a more restricted sense, forms the theo- 
retical basis of drug treatment. If it is to serve its full usefulness 
in explaining the ways and means by which pathological conditions 
may be influenced by drugs, it must constantly keep in closest relations 
with general pathology, i.e., the study of the various disturbances which 
occur in disease. These two sciences working together must endeavor 
to explain how pathologically disturbed functions of the different 
organs may be influenced by drugs and be brought back to the norm. 
Here lies their significance for clinical teaching and medical practice. 

Scientific drug therapy, as presented by us, consequently is dealt 
with, in so far as possible, in connection with the physician's point of 
view as to the seat and cause of pathological conditions. For this 
reason we have divided the drugs into two classes, organotropic (those 
influencing organs or their functions), and etiotropic (those acting on 
the causative agents of disease), and have thought it best to describe 
and analyze the organotropic pharmacological actions separately for 
each organ or functional system. 

It appears to us not at all disadvantageous that this method of 
presentation requires that we frequently must hark back to a considera- 
tion of physiological basic principles, for in view of the fact that physi- 
ology has been displaced from among the final subjects in the examina- 
tions for license, it becomes more important than ever that experimental 
pharmacology should refresh and keep alive the knowledge of physi- 
ology in the consciousness of the candidate for license. 

On the other hand, this necessitates the omission from this work of 
all notice of a number of pharmacological facts, which, while they 



iv AUTHORS' PREFACE 

possess value for the science of pharmacology, do not appear at present 
to be available as material for building the foundation of a scientific 
therapy. 

While the different chapters, as shown in the table of contents, have 
been written by one or the other of us, still there has been a constant 
cooperation and collaboration between us, which leads us to hope that 
we have prepared for the reader a homogeneous work. 

H. Meyer, 
R. Gottlieb. 



TRANSLATOR'S PREFACE 

It has been the translator 's aim to present a faithful rendition into 
English of the original work, and if in seeking to do this he has occa- 
sionally or frequently built up sentences which are unwieldy or un- 
English, he hopes that this will be borne in mind as extenuation there- 
for. Occasionally, where he has' thought it would be of value, he has 
interpolated comments or additions, which are regularly indicated in 
the text. 

J. T. H. 



CONTENTS 

CHAPTER I 

PAGE 

Pharmacology of the Motor Nerve-endings (Gottlieb) 1 

Depressants: Curare — General Discussions of Pharmacological Actions — 
Stimulants. 

CHAPTER II 

Pharmacology of the Central Nervous System (Gottlieb) 11 

Excitants — Strychnine — General Discussion of Alkaloids — Convulsants — 
Cerebral Excitants — Delirifacients — Depressants — Morphine Group. 
Alcohol-chloroform Group: Alcohol — General Anaesthetics — Ether — Chlo- 
roform — Combined Anaesthesia — Nitrous Oxide — Ethyl Bromide. 
Hypnotics of Alcohol-chloroform Group : Insomnia — Chloral — Other Hyp- 
notics. 

Relationship between Constitution and Pharmacological Action: Theory 
of Narcosis (Meyer) — Other Central Depressants — Aconitine — Magnesium 
Salts — Bromides — Valerian. 

CHAPTER III 

Pharmacology of the Sensory Nerve-endings (Gottlieb) 117 

Stimulants — Local Anaesthesia — Cocaine — Substitutes for Cocaine. 

CHAPTER IV 

Pharmacology of the Vegetative Nervous System (Gottlieb) 136 

The Sympathetic Nervous System — Autonomic or Parasympathetic 
Nervous System — Common Reaction to Nicotine — Antagonistic Func- 
tions of the Two Systems — Epinephrin a "Sympathetic" Drug — Auto- 
nomic Drugs. 

CHAPTER V 

Pharmacology of the Eye (Meyer) 144 

Pharmacology of the Retina — Of the Iris and Ciliary Muscles — Central My- 
driatics and Miotics — Peripheral Miotics — Physostigmine — Pilocarpine — 
Other Miotics — Peripheral Mydriatics — Atropine — Substitutes for Atro- 
pine — Cocaine — Epinephrin — Astringents and Corrosives — Abrin — Dionin 
and Peronin. 

CHAPTER VI 

Pharmacology of the Digestion (Meyer) 162 

Pharmacology of the Digestive Glands: Salivary Secretion — Reflex and 
Direct Excitation — Inhibition — Elimination by Saliva — Gastric Secretion — 
Stimulation and Inhibition — Pancreatic Secretion — Internal Secretion — 
The Secretion of the Bile; — Cholagogues — Elimination and Antisepsis — 
Other Liver Functions — The Secretion of the Intestinal Juice — Elimina- 
tion — Absorption in the Alimentary Canal — In the Stomach — In the Intes- 
tine — Absorption of Salts. 

Mechanics of Digestion: Deglutition — Movements of the Stomach — 
Emesis — Central Emetics — Apomorphine — Peripheral Emetics — Ipecac — 
Copper Sulphate — Zinc Sulphates — Tartar Emetic — Treatment of Vomit- 
ing — Normal Movements — Drugs Stimulating These — Inhibition of Gas- 
tric Movements — Atropine and Morphine. 

vii 



viii CONTENTS 

Movements of Intestines: Autonomic Drugs — Sympathetic Drugs — Atro- 
pine and Morphine. 

Cathartics: Classification — Cathartics Interfering with Absorption — Sa- 
t lines — Calomel — Cathartics Acting on Small Intestine — Castor Oil — 
Croton Oil — Jalap, Scammony, Colocynth, Gamboge, Podophyllin — 
Cathartics Acting on Large Intestine — Senna, Cascara, Rhubarb, Aloes, 
Phenolphthalein, Sulphur — Carminatives. 
Obstipants — Astringents — Tannin — Metallic Salts. 

CHAPTER VII 

Pharmacology of the Reproductive Organs (Gottlieb) 218 

Nervous and Chemical Correlation — Influence of Testicles and Ovaries — 
Erection — Yohimbin — Mammary Glands — Lactogogues — Elimination in 
Milk. 

Pharmacology of Uterine Movements — Peripherally Acting Drugs — 
Oxytoxics, Central and Reflex — Ergot — Hydrastis — Epinephrin — Hypo- 
physis Extracts. 

CHAPTER VIII 

Pharmacology of the Circulation (Gottlieb) 231 

Factors Controlling the Circulation — Methods of Investigation. 
Pharmacology of the Heart: Cardiac Functions — Actions on Centres of 
the Extracardial Nerves — Drugs Acting on Peripheral Vagus — Nicotine — 
Choline and Muscarine — Atropine — Physostigmine — Actions on Accelera- 
tor in Periphery — Cardiac Depressants — Cardiac Stimulants — Camphor — 
Ether — Alcohol — Epinephrin — Digitalis — Caffeine — Other Factors. 
Pharmacology of the Vessels: Central Vasoconstricting Drugs — Caffeine,' 
Camphor, etc. — Alcohol — Ether — Central Vasodilating Drugs — Amyl Ni- 
trite — Peripheral Vasoconstricting Drugs — Epinephrin — Digitalis Bodies — 
Peripheral Vasodilating Drugs — Capillary Dilators — Yohimbin — Caffeine — 
Local Applications. 

Pharmacology of the Circulation as a Whole: Theory of the Action of 
Digitalis — Practical Employment — Active Principles — Chemical Assay — 
Physiological Assay — Cumulation — Dosage — Preparations — Treatment of 
Cardiac and Vascular Depression — Treatment of Vasoconstriction. 

CHAPTER IX 

Pharmacology of the Respiratory System (Meyer) 332 

Actions of C0 2 and 2 — Direct or Central Stimulants — Respiratory Seda- 
tives — Morphine — Expectorants — Treatment of Asthma. 

CHAPTER X 

Pharmacology of the Renal Function (Meyer) 349 

Physiology of Diuresis — Factors Controlling Diuresis — Hydraemia — Blood 
Flow through Kidney — Caffeine Group — Digitalis Group — Agents Acting 
on the Tubules — Urinary Antiseptics — Alkalies — Atophan. 

CHAPTER XI 

Pharmacology of the Secretion of Sweat (Gottlieb) 369 

Physiology — Diaphoretics, Central and Peripheral — Antisudorifics. 

CHAPTER XII 

Pharmacology of the Metabolism (Meyer) 377 

General Considerations — Increased Assimilation — Altered Metabolism — 






CONTENTS ix 

The Effects of Body Temperature and of Light and Radiant Energy — 
Water and Salts — Alkalies — Acids — Thyroid — Iodine — Quinine — Sub- 
stances, Inhibiting Oxidation — Phosphorus — Arsenic — Antimony — Iron 
and Mercury — Lecithin — Certain Phases of Metabolism — Carbohydrate 
Metabolism — Purine Metabolism. 

CHAPTER XIII 

Pharmacology of the Muscles (Meyer) 422 

Physiology" "and Anatomy — Strychnine — Muscular Depressants — Stimu- 
lants — Caffeine — Alcohol — Alcohol as a Food — Testicular Extracts. 

CHAPTER XIV 

Pharmacology of the Blood (Meyer) 435 

Infusions — Iron — Manganese and Arsenic — High Altitudes — Agents Affect- 
ing the Leucocytes — Coagulation — Viscosity — Chemical Composition and 
Alkalinity — Toxicology of the Blood — CO and HCN — Haemolysis. 

CHAPTER XV 

Pharmacology of Heat Regulation (Gottlieb) 453 

Physiology — Fever — Action of Antipyretics in Fever — Cold Baths — Action 
of Antipyretics on Heat Production and Loss — Antipyrine Group — Quinine 
— Salicylates — Other Agents — Therapeutic Employment — Quinine — Anti- 
pyrine Group — Salicylic Acid Group. 

CHAPTER XVI 

Pharmacology of Inflammation (Meyer) 481 

Nature and Significance of Inflammation — Cutaneous Irritants — Exci- 
tants of Inflammation — Vascular Poisons — Caustics — Therapeutic Em- 
ployment and Mode of Action — Counterirritants — Vesicants and Sup- 
purants — Caustics or Escharotics — Inhibition of Inflammation — Analgesic 
Antiphlogistic Agents — Astringents — Lime Salts — Epinephrin — Quinine. 

CHAPTER XVII 

Etiotropic Pharmacological Agents (Gottlieb) 497 

General Antiseptics and Disinfection — Anthelmintics — Specific Disinfec- 
tants — Creosote in Tuberculosis — Quinine in Malaria — Salicylic Acid in 
Rheumatism — Arsenical Compounds in Protozoal Diseases — Mercury in 
Syphilis — Antitoxins — Vaccination against Rabies — Tuberculin — Serum 
Therapy — Toxins — Antitoxins — Ehrlich's Side-chain Theory — Antitoxic 
Sera — Tetanus — Diphtheria — Bacteriolysins — Agglutinins and Cytotoxins. 

CHAPTER XVIII 

Factors Influencing Pharmacological Reactions (Meyer) 561 

Solubility, Quantity and Penetrating Power of Drugs — Concentration in 
the Blood — Relation between Size of Dosage and Intensity of Effect — 
The Functional Condition of the Organs — Antagonism — Distoxication — 
True Antagonism — Immunity — Synergism — Hypersusccptibility — Anaphy- 
laxis^ — Experimental Therapy — Clinic and Laboratory. 



ILLUSTRATIONS 



FIG. PAGE 

1. Upper Part of M. gracilis Curarized, Lower Part before Operation 3 

2. Diagrammatic Representation of Spinal Cord (in color) 15 

3. Diagram of Intracentral Inhibitory Mechanism of Spinal Cord (in color) . . 17 

4. Forced Inhalation of Irritant Gas 61 

5. Comparative Effects on Blood-pressure of Chloroform and Ether 61 

6. Sudden Heart Death from Administration of Concentrated Chloroform Vapor 65 

7. Curve Indicating Depth of Sleep and Curves Obtained under Paraldehyde . . 87 
Diagram of Vegetative Nervous System (in color) 139 

8. Nerves and Fibres (in color) 146 

9. Monkey's Eye after Atropine 149 

10. Monkey's Eye after Eserine 150 

11. Innervation of Salivary Glands (in color) 162 

12. Secretion after Taking Food 170 

13. Cat's Stomach Filled with Bismuth and Potato Puree 189 

14. Pharmacological Action on Peripheral Sympathetic Organs (in color) 191 

15. Determination of Red-cell Content of Blood before and after Administra- 

tion of Salts 199 

16. Sympathetic Nerves and Nervus Hypogastricus (in color) 221 

17a. Normal, Dicrotic, and Tense Pulse 235 

176. Sphygmograms from Case of Lead Colic 236 

18. Williams' Frog-heart Apparatus . .• 239 

19. Experiments on Isolated Mammalian Heart (Method of Hering and Bock) 241 

20. Effect on Intestine of Stimulation of Splanchnic 243 

21. Suppression of Muscarine Standstill by Atropine 250 

22. Circulatory Action of Muscarine in Mammal 251 

23. Suppression of Chloral Standstill by Camphor in Perfused Frog's Heart . . . 256 

24. Effect of Epinephrin on Isolated Cat's Heart 260 

25. Effect of Injection of Suprarenal Extract 1 Minute 35 Seconds after Cessa- 

tion of Heart-beat 261 

26. Tracing from Frog's Heart 263 

27. Curves Obtained from Surviving Cat's Heart 264 

28. Increase in Variations of Intraventricular Pressure after Strophanthin, 

and Their Progressive Diminution 265 

29. Effect of Strychnine on Blood-pressure of Curarized Cat 273 

30. Effect Produced by Suprarenal Extracts on Blood-pressure and Volume of 

Different Organs 281 

31. Course of Vasoconstriction Produced by Serum from Carotid and by that 

from Suprarenal Veins 2S4 

32. Effects of Strophanthin on Blood-pressure and on Volume of Spleen and Leg 2S7 

33. Blood-pressure in "Heart-lung" Circulation before and after Digitalis 

Body 293 

34. Blood-pressure Curves Showing Effects of Digitalis in a Dog 295 

35. Changes in Ventricular Volume during Cardiac Cycle 297 

36a. Tense Pulse before and after Amyl Nitrite 328 

37. Pulse during Lead Colic and after Amyl Nitrite 329 

38. Antagonistic Action of Morphine and Atropine on Respiration 336 

xi 



xii ILLUSTRATIONS 

39. Respiratory Volume with Increasing C0 2 Tension of Blood 337 

40. Urinary Excretion in Dog under Varying Blood-pressure 349 

41. Secretion of Water by Tubules 353 

42. Effects of Caffeine on Blood-pressure and Renal Secretion in Chloralized 

Rabbit 361 

43. Effects of Caffeine on Secretion of Normal Right and Nerveless Left Kidney 362 

44. 45. Heads of Calves' Femur 406 

46. Rabbit's Femurs 410 

47. Nerve Stimulation by KC1 424 

48. Contractions 426 

49. Ergographic Curves 429 

50. Normal and Alcohol Curves 430 

51. Representation of Variation in Number of Red Cells in the Cu. Mm 436 

52. Influence of Fasting on Concentration of Blood 437 

53. Influence of Alcohol on Concentration of Blood 437 

54. Effect of Various Altitudes on the Number of Erythrocytes 445 

55. Changing Values of Head Production and Output Shown as Ordinates 457 

56. Normal Course of Puncture Hyperthermia 464 

57. Effect of Antipyrine on Puncture Hyperthermia 464 

5S. Effects of Morphine and of Antipyrine on Puncture Hyperthermia 465 

59. Antipyretic Effect of Antipyrine 469 

60. Antipyretic Effect of Quinine 470 

61. Tertian Malarial Parasites 528 

62. 63, 64 565 



PHARMACOLOGY 

CLINICAL AND EXPERIMENTAL 
CHAPTER I 

PHARMACOLOGY OF THE MOTOR NERVE-ENDINGS 

While all parts of the nervous system may be influenced, by 
drugs, the nerve-endings and the nerve-centres are much more sus- 
ceptible to such action than are the conducting paths. This is due 
partly to the scanty blood supply of the nerve-trunks, but chiefly to 
the fact that the medullated nerve-fibres are enclosed in sheaths and 
are thus protected from the action of the drugs, while the nerve- 
endings are not thus protected and are therefore more readily affected. 
However, this protection is not absolute, for, when exposed nerve- 
trunks are moistened with solutions of drugs or exposed to volatile 
gases, such as ether, choloroform, etc., which are soluble in the lipoids 
of the medullary portion of the nerve, stimulating or depressing 
actions result (Joteyko u. Stephanowska, Sowton and Waller). 

DEPRESSION OF MOTOR NERVE-ENDINGS 

Practically, however, pharmacological action on nerve-trunks is of 
importance only when a concentrated solution of a drug is applied 
to, or in the immediate neighborhood of, a nerve, as, for example, 
when cocaine is purposely so injected, or when a hypodermic of 
ether chances to reach a nerve-trunk, in which latter case most un- 
desirable harmful effects may result. 

After discussion of the pharmacology of the motor nerve-endings, 
thai (if I In' central nervous system, of the sensory nerve-endings, and 
finally that of the vegetative nervous system will be taken up in the 
order named. 

Curare and its readily analyzed actions form a good starting- 
point, fnr tin' study of the pharmacology of the motor nerve-endings. 
Although little or not at all used in therapeutics, it, should be useful 
as illustrating certain general conceptions of pharmacological action. 

The South American arrow-poison, curare (woorari, urari), is 
obtained from various poisonous plants of the family of Loganiacese. 
Different explorers, notably Humboldt (1799-1804), have told how 
the Indians prepared this substance by evaporating aqueous extracts 
of various plants, often adding to it all kinds of other substances. 

They also reported the enormous activity of the freshly prepared 
'^poison when it is introduced into wounds of men and animals. 

1 



2 PHARMACOLOGY OF MOTOR NERVE-ENDINGS 

Humboldt also noted that the flesh of animals thus poisoned could 
be eaten with impunity, and that wounds poisoned by curare could 
without danger be cleansed by sucking out the poison. Both of 
these observations indicated that when administered by the stomach 
it, as a rule, was inert. 

Active Principles. — AA 7 hen brought to Europe, this poison immedi- 
ately greatly interested physiologists, but, owing to the fact that its 
active principles readily undergo changes resulting in a diminution of 
their activity, it also proved far less powerful than the fresh curare. 

The physiological activity of curare obtained from different sources has 
been found to differ not only quantitatively but also qualitatively. Bohm 1 
showed that different alkaloids are contained in varying proportions in the 
three chief commercial varieties, tube curare, pot curare, and gourd curare, 
thus variously named from the different containers in which they are marketed. 
These alkaloids belong to two groups, the curines, possessing little or no true 
curare action, and the curarines, which produce the typical effects. The curine 
from tube curare is a cardiac depressant, and as, unfortunately, most of the 
commercial curare is of this variety, its unsatisfactory action is readily under- 
stood. 

(.'marine has not yet been obtained in crystalline form. Of the purest 
thus far prepared (Bohm 1 ) 1/100-1/50 of a milligram produces typical par- 
alysis in a frog. On the other hand, the curines, being heart poisons, do not 
produce true or typical curare effects but cause chiefly other disturbing effects. 
The more curarine and the less curine a curare contains, the more typical and 
uncomplicated by other effects is its action. 

When an effective dose of curare is injected into a frog, it soon 
drops its head, abandons its normal crouching position, and lies on 
its belly. At first, irritation causes a powerful muscular response, 
but soon the movements become weaker. The frog no longer jumps, 
and the respiratory movements of the throat muscles are the only 
movements observed after irritation. Finally, the frog becomes en- 
tirely motionless and no reflex movements result from even the 
strongest stimuli. The frog, however, is not dead, for the heart con- 
tinues to beat strongly. It is simply suffering from motor paralysis 
and, as the muscles still react readily to a direct stimulation, the 
cause of the paralysis must lie in some portion of the nervous system. 

Analysis of the Actions. — In the middle of the last century, 
Claude Bernard 1 and Kolliker 1 both correctly analyzed these 
effects and determined that the paralysis was of peripheral causation. 
By ligature of the iliac artery or by tightly binding the whole of the 
upper thigh, exclusive of the sciatic nerve, one hind leg of a frog 
may be cut out from the circulation and the blood will no longer 
reach the periphery in this limb, although its innervation is not dis- 
turbed. If curare be injected into a frog so prepared, the rest of the 
frog soon becomes completely paralyzed, but movements occur spon- 
taneously in this "isolated" leg and reflexly when the skin of any 
pai-t of the body is irritated. Stimulation of the cord or of the 
exposed sciatic nerve causes muscular contractions in this leg but 
not in the other. It is thus shown that the poison does not act on 
the central nervous system, but must produce its effects by acting 



CURARE 3 

on the nerves in the periphery. That this action is not on the nerve- 
trunks is proved by the fact that even after a nerve-trunk has lain 
for some time in a curare solution its conductivity is not impaired. 
It must, therefore, be concluded that the drug paralyzes the motor 
nerve-endings of voluntary muscles and does not produce any action 
on other organs. 

It is of interest that Fontana (1781) barely failed to recognize that the 
action of curare was one on the motor nerve-endings. However, as at that time 
the existence of nerve-endings had not been realized by physiologists, after con- 
sidering the hypothesis that this drug acted on the lowest portion of the 
motor nerves, he discarded it and located the curare action in the blood. 

The sensory nerve-endings and the sensory nerve-paths are not 
affected by curare, for, as mentioned above, in this experiment with 
the "isolated" leg, irritation of any part of the body which had been 
exposed to the action of the drug causes reflex movements in the 
"isolated" leg, which could occur only if the sensory nerve-endings, 
nerve-trunks, and the sensory tracts and the reflex mechanism in the 
cord were still functionally intact. 

The curare action, therefore, is limited to the motor end-organs, 
and the motor conduction paths remain, certainly for a time, capable 
of functioning. 

During the first few hours of the action of curare, that the very delicate 
intermuscular nerve-fibrils do not lose their power of conduction, was shown 
by Kiihne 1 in ingenious experiments. He succeeded in separating a muscle into 
two functionally independent parts and in curarizing the upper portion while 
the lower portion was protected by a tightly bound ligature. As, before entering 
the muscle, the nerve-trunk divided, sending branches to supply the two portions 
of the muscle, if the law of " conduction of impulses in both directions " holds 
good under these conditions, it should be possible for a stimulation of the 
nerve-fibres starting in the poisoned part of the muscle to pass up these fibres 
to the parent trunk and thence down the branch leading to the unpoisoned part 
of the muscle and to cause contraction of this part. As a matter of fact, in 
these experiments stimulation of the intramuscular filaments of the nerve in the 
poisoned half promptly and regularly caused contraction in the unpoisoned 
muscle. (Fig. 1.) 

The motor conduction paths are affected only 
after long-continued exposure to curare solu- 
tions (Kiihne, 1 Herzen, v. Bezold), but this is 
of absolutely no importance except in the frog. 

It thus appears that curare interposes to 
centrifugal impulses a resistance at a point be- 
tween the motor nerve-fibres and their final ter- 
minal organs in the muscles, a resistance which 
cannot be overcome if the curare action be fully 
developed. During the early stages of the ac- 
tion, this growing resistance manifests itself by 
;i progressive tendency to fatigue of the motor 
nerve-endings, so that under rhythmic stimula- Fia.i.—z,, upper part of 
tin,, the contractions grow shorter and shorter K?$e?p£t Srtra&S 
| Boh m , 2 Santcsson 1 ) . 




rizcd. 



4 PHARMACOLOGY OF MOTOR NERVE-ENDINGS 

As is to be expected the results of the paralysis caused by curare 
differ materially in frogs and in warm-blooded animals. Curarized 
frogs can continue to live for days, for, even after all respiratory 
movements have ceased, the respiration through the skin can supply 
all the oxygen necessary for their metabolism. A satisfactory circu- 
latory function is maintained and renal secretion continues and at- 
tends to the elimination of the poison. Curare poisoning may, there- 
fore, be caused in a second frog by injecting the urine of a curarized 
one (Jakabluizy) . 

Only much larger dose9 (30 times that necessary to cause paralysis) are 
fatal in frogs, these larger doses interfering with the circulation and thus 
preventing the secretion of the urine and the elimination of the poison. Tillie 
observed recovery from a paralysis which had been induced by smaller doses 
and had lasted 25 days. 

In mammals the results of this primary action of curare are quite 
different, for in them the muscular paralysis causes asphyxia and 
death unless artificial respiration is instituted. However, the respira- 
tory muscles are the last to be affected, so that, by administering the 
proper dose, it is possible to keep a rabbit alive for hours with all 
its muscles paralyzed except the diaphragm. 

If artificial respiration is maintained and the curare be of good 
quality, both heart and vessels are entirely unaffected by any but 
very large doses, and, as the poison is excreted through the kidneys 
fairly rapidly, mammals too may recover after the paralysis passes 
off. Only after larger doses are other functions than those of the 
motor nerve-endings affected. "Very large doses lower the blood- 
pressure by a depressing action on the peripheral vasoconstrictor 
mechanism {Tillie). When this action is fully developed, neither 
stimulation of the sciatic nor asphyxiation causes a rise in the blood- 
pressure. Large doses also weaken the cardio-inhibitory action of the 
vagus, but the motor mechanism of the heart is unaffected. The 
motor nerve-endings of smooth muscle are also but little affected 
(Bidder), the intestine remaining excitable and peristalsis continu- 
ing even after extremely large doses. 

In connection with its use in physiological experiments, the ques- 
tion as to the nature of the action of curare on the central nervous 
system is of great interest. In Steiner's experiments with fishes, a 
narcosis of the cerebrum was apparently induced, but it is doubtful 
if the cerebrum of higher animals is appreciably affected by curare. 
The spinal cord is certainly not depressed. On the contrary, accord- 
ing to Tillie, larger doses cause an increase in its reflex excitability 
similar to that caused by strychnine. In mammals an increase in the 
excitability of the vasomotor centre occurs quite early (S oilman n and 
Pilcher) . 

The effects of curarization on the temperature and metabolism (0. Frank 
u. F. Voit) are to be considered simply as a result of the abolition of the 



CURABE 5 

activity of all voluntary muscles. Glycosuria, which, has been observed both in 
animals and in man after injections of curare, is an inconstant phenomenon 
depending on unknown causes ( Morishima ) . 

It has long been known that curare administered orally is entirely 
ineffective, even when given in doses much larger than those which 
are lethal when given hypodermically. Formerly this lack of action 
when the drug was thus) administered was explained by the assump~ 
tion that the acid gastric juice destroyed or changed the curare. 
Although the acid of the gastric juice has a deleterious action on the 
easily decomposed curarin (N. Zuntz), this is not pronounced enough 
to explain the great difference between the action of the drug when 
given by mouth and when injected subcutaneously. Nor is it due to 
its not being absorbed from the alimentary canal. Ber-nard 2 and 
Hermann both showed that the comparatively slow absorption from 
the alimentary canal and the comparatively rapid excretion by the 
kidneys account for the lack of action when the drug is administered 
orally, for, if the renal arteries be ligatured and the drug then in- 
troduced into the stomach, typical curare effects develop-. 

GENERAL FACTORS AND PRINCIPLES INVOLVED IN THE 
PHARMACOLOGICAL ACTION OF POISONS AND DRUGS 

Before going farther, it seems advisable to bring forward certain 
general factors and principles involved in the pharmacological action 
of poisons and drugs. 

By the action of a drug or poison we understand the aggregate 
of the alterations which it causes in the functions of the whole body. 
The action of curare is directed with unusual precision against a 
single kind of organ, the motor nerve-endings. This we call an 
elective action. When injected subcutaneously, curare does not 
act on the subcutaneous tissues at the point of injection, nor, when 
given intravenously, does it act on the blood-vessels. It has thus no 
local action, but the motor nerve-endings in the whole body are 
acted upon wherever sufficient amounts of the drug are carried by the 
blood. This we call systemic action. 

Just as the ordinary dose affects only the motor nerve-endings, 
BO too the action of a dose many times larger is limited to these same 
organs, all other cells in the body being unaffected or nearly so. 

With many other drugs having an elective systemic action, we 
find a somewhat different behavior; for example, with an increase 
of thai minimal dose of atropine which diminishes glandular secretion, 
the pupils dilate and the pulse-rate increases, ; i rid, after a somewhat 
L'fr;iter increase in the dose, still other functions are affected. Here 
the first effect is soon followed by effects due to actions on other 
organs, while with curare the systemic action (except with very large 
is exerted on a single kind of organ, as it is in a very high 
degr 'leeiive. Curare also illustrates well how the resulls of the 



6 PHARMACOLOGY OF MOTOR NERVE-ENDINGS 

same pharmacological action may differ in different species of animals, 
the frog surviving for days in spite of complete paralysis of all volun- 
tary muscles, whereas, in warm-blooded animals, asphyxia results from 
this identical action. Here we have illustrations of primary or direct, 
and secondary or remote or indirect pharmacological actions or 
illustrations of pharmacological actions and their effects. 

THE NATURE OF PHARMACOLOGICAL ACTIONS 

The analysis of the curare action as given above consists in a de- 
termination of its seat of action in a physiological sense, such deter- 
mination of the seat of action being always the first problem in 
pharmacological research. The nature of the action in the case of 
curare paralysis, as also in the case of all other pharmacological ac- 
tions, is to be considered as a chemical or physico-chemical interaction 
between the drug and the constituents of the cell. In the case of curare, 
as in most cases, it is not yet known which elements of the functioning 
cell are involved in the reactions. However, this lack of precise 
knowledge in no way affects the conception that assumes a chemical 
or physical change in the affected organs whenever a pharmacological 
action takes place. In some instances it is known with what cell 
elements the drug reacts; for example, in the case of the action of 
carbon monoxide on the blood-cells, it is the haemoglobin which enters 
into the chemical reaction. In other cases the chemical properties of 
the drug enable us to deduce with considerable precision the chemical 
substances in the cell which are especially involved in the chemical 
reaction occurring. In this way the cytotoxic action of oxalic acid 
has led to a recognition of the importance of the calcium salts for 
cell life. In the case of the alkaloids, on the other hand, we know 
only the place where the reaction takes place but not the reacting 
constituents of the protoplasm. 

Even in the analysis of the action of curare, it must be admitted 
that the determination of the seat of action is not absolutely definite, 
for the nervous end-organs are complex structures containing nerve- 
fibrils which pass into the true end-organs, the nerve-plates, these last 
finally send branching filaments into the muscle-cells (Hcrzen, Joteyko, 
Langlcy). 

In all cases an alteration of the protoplasm must be assumed, 
and we must conceive that this protoplasm attracts to itself the drug 
present in a definite, although very moderate, concentration in the 
blood. Curare gives us a good example of this dependence of the 
reaction between the protoplasmic constituents and the drug on a 
definite adequate concentration of the drug in the blood and the 
tissue fluids, the so-called "threshold value." If, after subcutaneous 
or intravenous injection, the concentration of the drug in the blood 
reaches this adequate concentration rapidly enough, the chemical or 



CURARE 7 

physical reaction occurs and the pharmacological reaction results. If, 
however, the same dose distributes itself throughout a larger animal, 
or if it enters the blood gradually and at the same time is removed 
from it by the activity of excretory organs, as for example when 
curare is absorbed from the stomach and excreted by the kidney, then 
this adequate concentration in the blood is not attained and the 
pharmacological action does not occur. 

Once the curare has combined with the nerve-endings it remains 
combined for a considerable time notwithstanding its rapid disap- 
pearance from the blood. Here, too, in the stability of this combination, 
we have the expression of a chemical or physico-chemical affinity be- 
tween the protoplasmic elements and the drug, but we have no exact 
knowledge of the nature of this affinity. At first sight the gradual 
disappearance of the curare paralysis appears quite as puzzling as its 
development. In CO poisoning the return of function is explained 
by the dissociation of the* CO haemoglobin, which begins as soon as 
the partial pressure of the CO in the blood-plasma — i.e., the concentra- 
tion in the neighborhood of the susceptible cell — diminishes below a 
certain level or is reduced to zero. In a similar manner — that is, by 
the conception of the combination of the drug with the cell sub- 
stance as a reversible process — we must explain the gradual return 
of function in other cases, which have thus far not been capable of 
closer analysis (Bohm 2 ). 

Therapeutic Use of Curare. — Many attempts have been made 
to use curare therapeutically, but without success. It might appear 
that it would be advantageous to use it to prevent convulsions due to 
an abnormal excitability of the central nervous system. Inasmuch as 
the respiratory muscles are the last to be paralyzed, it is possible, at 
least in experiments on animals, to maintain, even without artificial 
respiration, a degree of curare action which prevents ordinarily effec- 
tive doses of strychnine from causing convulsions. Such treatment 
of strychnine poisoning, although entirely symptomatic, if combined 
with the removal of the poison by means of stomach lavage and with 
stimulation of diuresis, might be the means of saving life, for ex- 
haustion of the vitally important nervous centres may result from the 
convulsions. In man, too, by prevention of convulsions by the use of 
curare, life might be saved in those cases of tetanus and rabies whore 
the body is able to overcome the infection. As a matter of fact, 
in a number of such cases, a cessation or diminution of the force and 
frequency of the convulsions has followed the use of curare (L. Vella, 
Busch, F. A. Hoffman, Berg ell in tetanus, Offcnberg, Penzoldt in 
rabies.) If this treatment be adopted, a complete paralysis of all the 
motor nerve-endings must be avoided, for, if the respiratory muscles 
be paralyzed, long-continued artificial respiration will be necessary 
and this alone '-.'in jeopardize life. Unfortunately, owing to the 



8 PHARMACOLOGY OF MOTOR NERVE-ENDINGS 

differences in the activity of different specimens of curare and their 
tendency to deteriorate, even physiologically assayed preparations 
cannot be used with any certainty as to dosage. 

Many other substances resemble curare in their action, and in 
their study certain interesting relationships between chemical con- 
stitution and physiological action have come to light. 

The characteristic action of almost all ammonium bases is the paralysis 
of motor nerve-endings. This is not possessed by chloride of trimethyl-ammonium, 
a tertiary base (Santesson u. Koraen), but the salts of tetramethyl-ammonium 
and those of the tetraethyl-ammonium (Rabuteau, Jodlbauer, Jordan), in ac- 
cordance with the quadrivalency of these liases, possess this action. Moreover, 
in the case of many alkaloids, such as strychnine, morphine, quinine, etc., their 
transformation into tetrabasic substances, such as methylstrychnine, methyl- 
morphine, etc., endows them with a more or less marked curare action {Broun 
and Fraser). In this connection, it is of interest that curarin is tetrabasic, while 
curine, which does not possess this characteristic action, is tribasic, but acquires 
it when methylated. 

BkCv. 

H 3 C— /N, trimethvlamine, a tertiary base. 
H 3 C/ 

HsC\ 

H3C -)N, I, trimethylamine hydroiodate. 

H 3 C/ I 

H 

np KiC^ 

\ H. C ^^ 

HsC-)N + ICH3 = tjc^^ — I> tetramethylanimonium iodide, a quaternary base. 



acil JCH, Htf^CH, 



N +ICH,= N 1 



CH 3 CH3 CH 3 

Tertiary Quaternary 

onibination. combination. 



It would appear, therefore, that the power of paralyzing motor nerve- 
endings is a property possessed especially by quaternary bases. This is ap- 
parently not due to their containing certain elements or groups, but rather to 
the increased basicity resulting from the change from a tertiary to a quaternary 
base (Fiihner), for* the analogous bases, which in place of nitrogen contain 
arsenic (Bilrgi) , antimony, phosphorus (Yulpian, Lindemann), iodine (Gottlieb) , 
or sulphur (Curci), (arsonium, stibonium, phosphonium, ionium, and sulfine 
bases), act like curare. It would be a mistake, however, to conclude that only 
this especial type of base possesses curare action, for the same action is exerted 
by a group of bases which are not quadrivalent (chinoline, pyridine, piperidine, 
and others) ( il/ oore and Prow), while non-basic substances, — e.g., camphor in 
the frog, — and lastly certain poisons of animal origin, such as the venom of the 
cobra and of the spectacled snake, also produce curare-like actions (Yollmer, 
Arthus). It is, however, probable that these substances, which are chemically so 
different, do not all act on the same elements or substances in the nerve- 
endings but on chemically different substances or elements in them. 



STIMULANTS OF MOTOR NERVE-ENDINGS 9 

STIMULATION OF MOTOR NERVE-ENDINGS 

The motor nerve-endings in striped muscles are also susceptible 
of excitation by chemical substances. This has long been known 
of guanidin (Gergens u. Baumann), while the fibrillary muscular 
twitchings caused by physostigmine are also due to excitation of the 
motor nerve-endings (Rothberger). Of especial interest is the 
reciprocal antagonism of curare and physostigmine (Rothberger, Pal). 
Animals poisoned by curare to the degree of complete cessation of 
respiratory movements, in which indirect muscle excitability (by 
centripetal stimulation of the sciatic) has disappeared, after the 
intravenous administration of physostigmine, show spontaneous res- 
piratory movements and normal muscle excitability, while the adminis- 
tration of a fresh dose of curare again brings about complete 
paralysis. 

One could think of this play of antagonism between these two 
drugs as resulting as follows: 

As physostigmine possesses a similar affinity for the nerve-endings, 
it displaces curare from its combination with these structures. Ac- 
cording to the doses administered, — that is, in accordance with the 
effective amounts present in the cells, — the opposite action may occur, 
curare replacing the physostigmine. It is, however, also possible that 
the two drugs act in different places or on different substances in the 
terminal nervous organs, and that curare places, as it were, a resist- 
ance coil in the end-plates while physostigmine increases the excita- 
bility of still more peripherally situated portions of the terminal 
organs. If the latter hypothesis represents the facts, a motor impulse, 
although able to pass through a portion of the end-organ which had 
been rendered more resistant by curare, would reach the terminal 
portion of the nerve in the muscle-cell only in such diminished force 
as not to cause an effective excitation. If, however, these terminal 
portions had been rendered more excitable by physostigmine, even 
the weakened impulse would produce an effect, while a further in- 
crease of the interposed resistance, resulting from further dosage with 
curare, would prevent entirely the passage of motor impulses to this 
terminal portion or weaken them to such a degree that they would no 
longer be effective. Certain other bases, among them choline, over- 
come the curare paralysis by an action similar to that of physostigmine 
(Rothbt rger, Pal). 

BIBLIOGRAPHY 

Abderhalden u. Mnller: Med. Klinik., 1010, No. 22. 

Artlms: Compt. rend, de L'acad. des sciences, 1910, vol. 151, p. 91. 

Bergell, P., a. Levy: Therapie der Gegenwart, L901, p. 396. 

1 Bernard, CI., ■ •( Pelouze: Compt. rend., 1850, vol. 31, p. 5:?:}; 1856, vol. 43, p. 

824; Lecons but lee effects des substances toxiques, Paris, 1857. 
'Bernard, CI.: Bevue des emirs seientifiques, 1805, No. 11. 
\. Bezold: Arch. I". Anat. u. Phys., 1860, p. 387. 
Bidder: Arch. f. Anat. u. Phys., 1865, p. 337. 



10 PHARMACOLOGY OF MOTOR NERVE-ENDINGS 

1 Bohm, R.: Beitrage zur Physiologie zu C. Ludwigs, 70 stem Geburtstag, Leip- 
zig, 1887, p. 173; Abhandlungen d. Kgl. sachs. Akad. d. Wissensch., 1895, 
vol. 1, p. 410, vol. 22, 1897, vol. 24, 1897 ; Arch. d. Pharmazie, 1897. 

- Bohm, R.: Arch. f. exp. u. Pharru., 1894, vol. 35, p. 16; 1910, vol. 63, p. 177. 

Brown and Fraser: Proc. Roy. Soc, Edinburgh, 1809, p. 500. 

Biirgi: Arch. f. exp. Path. u. Pharm., 1906, vol. 56, p. 101. 

Busch, W.: Niederrhein. Gesellsch. f. Natur. u. Heilkunde, Bonn, 1867. 

Curci, A.: Arch, di farm, e ter., 1896, 4. 

Fontana: Abhandlg. iiber das Viperngift, die amerik. Gifte, etc., Florence, 1781, 
translated, Berlin, 17S7. 

Frank, O., u. F. Voit: Zeitschr. f. Biologie, vol. 42, p. 309. 

Fiihner: Arch. f. exp. Path. u. Pharm., 1907, 59. 

Gergens u. Baumann: Plliiger's Arch., 1876, 12. 

Gottlieb: Ber. d. D. cheni. Ges., 27, p. 1599. 

Hermann, L. : Arch. f. Anat. u. Physiologie, 1867, p. 64. 

Herzen: Intermed. de Biolog., 1898, 15. 

Hoffmann, F. A.: Berl. klin. Wochenschr., 1879, p. 637; Arch. f. klin. Medizin, 
1889, vol. 45, p. 107. 

Humboldt: Reisen in den iiquinoktialen Gegenden Amerikas, 1799-1804, 1860, 
vol. 4, p. 80. 

Jakabhazy: Arch. f. exp. Path. u. Pharm., 1899, vol. 42, p. 10. 

.Todlbauer: Arch, intern, de Pharmacodynamic, 1900, vol. 7, p. 183. 

Jordan: Arch. f. exp. Path. u. Pharm., 1877, vol. 8, p. 15. 

Joteyko, J.: Inst. Solvay, Trav. 4, 1901. 

Joteyko u. Stephanowska : Institut Solvay, Travaux Tome, 4. 

Kolfiker: Compt. rend., 1856, vol. 43, Arch. f. pathol. Anatomie, 1856, vol. 10, p. 3. 

1 Kiihne, W. : Ueber die Wirkung des Pfeilgiftes auf die Nervenstamme, Heidel- 

berg, 1886, Festschrift des nat. med. Vereins. 

2 Kiihne: Arch. f. Anat. u. Phys., 1860, p. 477. 
Langley: Journal of Physiol., 1905, vol. 33. 
Lindemann: Arch. f. exp. Path. u. Pharm., 1898, 41. 
Moore and Prow: Journ. of Phvsiologv, 1898, vol. 22. 
Morishima: Arch. f. exp. Path. u. Pharm., 1S99, vol. 42, p. 28. 
Pal, J.: Zentralblatt f. Phvs., 1910, No. 1; 1900, vol. 14, p. 255. 
Penzoldt: Berl. klin. Wochenschrift, 1882, p. 33. 

Rabuteau: Compt. rend. Ac. d. Sciences, 1S73, vol. 76, p. 887. 
Rothberger, J. C: Arch. f. die. ges. Phys., 1901, vol. 87, p. 117, vol. 92. 
Santesson, C. G.: Arch. f. exp. Path u. Pharm., 1894, vol. 35, p. 23. 
Santesson, C. G., u. G. Koraen: Skandinav. Arch. f. Physiologie, 1900, vol. 

10, p. 201. 
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2 Steiner: Das amerikanische Pfeilgift, Curare, Habilitationsschrift, Erlangen, 

1877. 
Sowton and Waller: Journ. of Phvs., 1898, Suppl. 23. 
Tillie, J.: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 1. 
Vella, L.: Comptes rend. Acad. Sciences, 1859. vol. 49, p. 330. 
Vollmer: Arch. f. exp. Path. u. Pharm., 1893. vol. 31. 
Vulpian: Arch, de phvs. Norm, et Path., 1868, 1. 
Zun'tz, N.: Pliuger's Arch. f. Physiol., 1891, vol. 49, p. 437. 



CHAPTER II 
PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM 

In the study of the pharmacology of the motor nerve-endings, it 
has been shown that in these nerves the capacity of transmitting 
centrifugal impulses to the muscle-cells may be depressed or dimin- 
ished by curare or increased by other substances. In all other nervous 
organs also and especially in the nervous centres, drugs and poisons 
may cause stimulation or depression, but never a qualitative change 
of function. However, although pharmacological actions in the cen- 
tral nervous system may consist only in depression or stimulation 
of nervous elements, it would be a mistake to conclude that there 
can, therefore, be but two types of pharmacologically active sub- 
stances, of which one increases while the other depresses the activity 
of the whole central nervous system, as exemplified by the old 
classification of sedatives and excitants. 

Different drugs, even though acting on the central nervous system 
in but one sense, differ much from each other on account of differ- 
ences in the order in which their actions on different functions de- 
velop, this order being characteristic for each drug or group of drugs. 
Owing to the different susceptibility of different parts of the central 
nervous S3 r stem to each individual drug, there results a great variety 
in the effects which may be produced. 

Often certain parts are so much more susceptible to the action of 
a drug than all other parts of the central nervous system, that from 
a therapeutic point of view only the action of this portion need be 
considered. For example, apomorphine in certain dosage acts directly 
only on the vomiting centre, leaving all other parts of the central 
nervous system practically unaffected, while small doses of morphine 
act almost exclusively on the function of pain perception (probably 
located in the cerebral cortex) and on the respiratory centre, its 
numerous other actions on the other centres resulting only from larger 
doses. Quite as sharply limited are the primary effects of numerous 
other drugs, and, as a result of the differences in the sensibility of 
the different elements which are affected, the whole picture of the 
pharmacological action of each drug is distinguished by the char- 
acteristic ordor in which changes occur in the different functions. 

The wonderful number of varieties of drug actions is also due 
to the fact that different parts of the central nervous system may not 
only differ quantitatively in their susceptibiliy to a given drug, but 
also to the fact that often enough certain centres may be excited and 
others depressed by identical doses of a given druor. Such a combina- 
tion of depression of certain functions and stimulation of others 

11 



12 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

is very commonly caused by toxic doses of those drugs which act 
especially on the central nervous system. Conditions varying from 
those resembling tipsiness with moderate excitement to those with 
most violent delirium or convulsions or with complete loss of con- 
sciousness are examples of such pharmacological actions, and are 
observed, for example, in atropine or in camphor poisoning. 

Numerous poisons have the peculiar property of causing, in the later 
stages of their action, or in larger dosage, a depression of those very cen- 
tres which they primarily stimulate. The action of prussic acid on the 
respiratory centre is a typical example of such behavior. Such observa- 
tions have occasioned much discussion as to whether or not this is a gen- 
eral law, — that is, whether every chemical irritation must in the begin- 
ning cause a stimulation. Inasmuch as no increase in the excitability of 
the nerve-endings can be observed at the commencement of the curare 
action nor in that of the respiratory centre at the beginning of the 
morphine action, it is not possible to conclude that this is a universal 
rule. The qualitative differences in the reactions and the quantita- 
tive differences in the susceptibility of the different but functionally 
related tracts of the central nervous system may be explained by the 
justifiable assumption that their protoplasm possesses different 
chemical and physical affinities for different drugs. However, our 
knowledge of the chemical physiology of the central nervous system 
is too incomplete to permit even rough guesses as to the nature of 
these affinities. From these differences in their chemical behavior 
toward the different drugs, it may be concluded that probably each 
nervous protoplasmic element which possesses a special function has 
certain peculiarities in its composition. The elective absorption of 
dyes — e.g., the vital staining with methylene blue — is a visible demon- 
stration of such differences in the affinities of different elements of the 
central nervous system. 

From the above, it is evident that the analysis of pharmaco- 
logical actions in the central nervous system will consist mainly 
of a determination of the points or functions acted upon, and of the 
order in which the different ones are affected. It seems well to start 
with a consideration of a stimulating pharmacological action, that of 
strychnine. 

STRYCHNINE 

Strychnine and a second much less active alkaloid, brucine, occur 
chiefly in various strychnos varieties (order Loganiaceas) and especi- 
ally in the seeds, wood, and bark of Strychnos Nux- vomica, indigenous 
in Southern Asia. Nux vomica, the dried seed of this tree, contains 
about 1.3 per cent, of strychnine and 1.7 per cent, of brucine. 

The bark contains even larger quantities of brucine, while the 
seeds of Strychnos ignatii, S. tieute, and other strychnos varieties 
contain as much as 2 per cent, of strychnine and also brucine. Some 
Malay tribes have used these in the preparation of arrow-poisons. 



STRYCHNINE 13 

Strychnine itself is an alkaloid, crystalline, efflorescent, and odor- 
less, but with a very bitter taste. It is poorly soluble in water and 
may be extracted from it by chloroform. Its salts are readily soluble 
in water, the sulphate being the one most used. When dissolved in 
concentrated H 2 S0 4 , strychnine gives, on addition of a trace of 
potassium bichromate, a violet color, which changes gradually to 
blue and then to green. 

The dominant action of strychnine is essentially an elective one 
on the reflex arcs in the central nervous system. If the reflexes are 
depressed as a result of pathological conditions, small doses of strych- 
nine may restore them to their normal condition, while toxic doses 
cause such an exaggerated irritability of the reflex mechanism that a 
reflex causes not only the ordinarily resulting normally coordinated 
movements occurring with abnormal intensity, but also other similarly 
exaggerated movements not normally resulting from such reflex. 
Normally, excitation of reflexes in the cord causes responses of 
various sorts, occurring according to fixed laws, so that, after stimula- 
tion of a given sensory nerve, certain movements and combinations 
of movements occur. When the action of strychnine has fully de- 
veloped, however, each single stimulus affecting the sensory organs 
causes a simultaneous contraction of all the skeletal muscles. 

Action in the Frog. — If 1/10 to 2/10 mg. of strychnine be in- 
jected into a frog, he soon shows an abnormal reaction whenever he 
is touched. While a normal frog, if lightly touched, does not move 
at all, and responds to stronger tactile stimuli only when they affect 
especially sensitive parts, after strychnine the very lightest touch is 
enough to cause violent reflexes. Slight shaking, which ordinarily 
is without effect, causes a pronounced muscular response, for the ex- 
citability of the reflex mechanism has been increased. Finally, any 
sensory stimulus produces a tetanic convulsion. 

By tetanus is meant a tonic contraction of all the skeletal muscles, 
lasting seconds or minutes, which is caused by a rapid succession of 
single muscular contractions. The individual convulsions may be 
separated from each other by longer or shorter periods, which, how- 
ever, may be so short that for a considerable period the body remains 
absolutely stiff and motionless. Inasmuch as, when all the muscles 
contract simultaneously, the extensors overcome the flexors, the ex- 
tremities and the trunk both assume the position of extension. 

A frog may lie for many days in this condition, as the respiration 
through the skin suffices for its sluggish metabolism, and as the 
tetanus itself, even when long continued, does not kill the frog. When 
produced by other poisons, such as tetanus toxine or certain poly- 
sulphides (Ilarnack), the tetanus may last for weeks and the frog 
• Milt inn,- to live. Small doses of strychnine also may cause a con- 
dition of maximally increased reflex excitability which lasts for from 
8 to 14 davs, during which every stimulus excites a tonic convulsion 



14 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

(Bongers). As somewhat larger doses of strychnine rapidly cause 
death in frogs, it is, therefore, clear that the fatal result is due not 
to the tetanus itself, but to other actions of strychnine which will be 
discussed later. 

A closer analysis of the action shows that its seat is in the 
cord. Its central nature is demonstrated by the fact that a leg isolated 
from the circulation before the injection of the drug is, like the 
others, involved in the convulsions, while as soon as its nerves are 
severed this is no longer the case (J. Mutter, Kblliker). The con- 
vulsions in a decerebrated frog differ in no way from those in an intact 
one, but, on the other hand, if the spinal cord be destroyed, the tetanus 
ceases. It follows that the chief seat of the action of strychnine lies 
in the cord, but this does not exclude the possibility that strychnine 
increases reflex excitability in the higher parts of the central nervous 
system as well as in the cord. 

That the tetanus is a convulsion of reflex origin and is not caused 
by direct stimulation was demonstrated in 1846 by Hermann Meyer, 
who observed that after division of all the posterior nerve-roots in 
frogs, convulsions did not occur, while the slightest touch to one of the 
central stumps of the roots caused most violent convulsions. The con- 
vulsions cease and the frogs remain relaxed if the skin be anaesthetized 
by painting with a solution of cocaine, all sensory stimulation via the 
nerves of touch being thus prevented (Poulsson) . Moreover, after very 
small doses, 1/50 to 1/100 mg., the simple avoidance of all stimulation 
or other irritation is sufficient to prevent the outbreak of convulsions. 
It is thus clear that the central reflex mechanism has been rendered 
immensely more sensitive to the normal physiological stimuli and that 
a direct stimulation of the motor ganglia in the anterior horns is not 
produced by the drug. 

This might be concluded simply from the character of the muscular 
contractions in strychnine convulsions, for these are not irregular or 
fibrillary twitchings, but are coordinated simultaneous contractions of 
entire groups of muscles. From what is known of the structure of the 
spinal cord, such contractions can result only with the aid of receptive 
neurons which are everywhere connected with one another by countless 
anastomoses and collaterals and which, when normally or abnormally 
stimulated, send their messages to motor neurons lying more or less 
distant from them, according as the paths are open for their passage 
or are more or less obstructed. On the other hand, motor neurons are 
incapable of independently transmitting exciting stimuli to each 
other (Exner 1 ), for no one has ever, by stimulating a motor nerve, 
succeeded in causing stimulation in another motor neuron. These con- 
ditions and relationships are schematically illustrated in Fig. 2. 
Houghton and Muirhead have also brought experimental proofs, based 
on these anatomical facts, that strychnine can act only on the 
branching receptive portions of the reflex arc. 



STRYCHNINE 



15 



If a trace of strychnine is placed on a limited portion of the exposed cord 
of a frog in which the blood and lymph circulation have been abolished, after 
a few seconds the following phenomena are observed. If a portion of the skin 
corresponding in its nervous supply to the poisoned segment of the cord be 
touched, a convulsion involving the whole animal occurs. If, however, any other 
part be touched, only the usual reflex movements result, and even the muscles 
controlled by the poisoned segment react in an entirely normal manner. Inas- 
much as the discharge of nervous energy causing contractions of all the muscles 
spreads only from the poisoned segment of the cord, that is to say, produces 
in all the unpoisoned motor cells of the anterior horn a stimulus resulting in 
tetanic contraction of the muscles, and as this can 
result only through the agency of the receptive cell 
mechanisms and their manifold anastomoses, it neces- 
sarily follows that these receptive cells are the seat 
of the abnormally violent and unrestrained discharge 
of nervous energy. 

At a later day, Baglioni 1 , in certain most instruc- 
tive experiments, obtained entirely similar results,^ 
using an isolated nerve and spinal cord preparation 
connected only with the hind legs. Under these con- 
ditions he found that strychnine acted only when placed 
on the dorsal side of the cord and not when placed on 
the ventral surface. An apparent contradiction of 
these views is furnished by an experiment of Sherring^. 
ton. The cord of a dog was isolated from all external 
impulses by cutting it across and dividing all the 
posterior spinal nerve-roots. After such preparation 
strychnine caused typical tetanus, even six weeks later 
when all the afferent neurons had completely degener 
ated (H. Meyer, unpublished experiments). > 

The contradiction is, however, only an apparent 
one, for of the mechanisms which transmit stimuli, only 
those neurons coming from the periphery and those com 
ing from the brain degenerate, while the independent 
" relay cells " ( ttchaltzellen, Exner's ■ a-cells ) with their 
continuations remain unaffected. These cells accordingly 
must be able to receive chemical stimuli from the blood 
or mechanical ones resulting from vibration and to co- 
ordinate and transmit them to the cells in the anterior 
horns. These " shunting " neurons (Schaltneurone) may 
be assumed to be the seat of the strychnine action. 

From consideration of these various phenomena, it may then be 
concluded that strychnine affects the receptive neurons of the cord 
in a special fashion and with a double effect : firstly, in place of normal, 
temporary, and sub-maximal contractions, only maximal and persisting 
contractions result from reflexes; and, secondly, these reflex tonic 
muscular contractions are not confined to that muscle group which is 
normally controlled by the stimulated .sensory neuron, but they involve 
all the muscles of the body and, as should be especially noted, even 
the antagonistic muscles. 

Theory of the Action of Strychnine. — For the better under- 
standing of these phenomena, one may assume that certain inhibitions 
in the receptive organs of the cord are removed by strychnine. It is 
very probable that in the sensory receptive cells there are certain 
inhibitory mechanisms, which ordinarily prevent the immediate dis- 
charge of aU their stored-up energy whenever they are stimulated. 




Fig. 2. — Diagrammatic re- 
presentation of spinal 
cord. Blue: Receptive 
cells and tracts. Red: 
Motor cells. 



16 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

For this reason, they function only intermittently, or, as Baglioni 2 
expresses it, these sensory cells have a refractory period, in contra- 
distinction to the motor ganglion cells in the anterior horns, which 
when stimulated can discharge energy continually (Birge, Bagliom 3 ). 
This is the reason why, under normal conditions, a tonic contraction 
of a muscle can never be caused reflexly, — that is, though the sensory 
tracts, — but is readily induced by direct stimulation of the motor 
ganglia. If this sensory mechanism be so affected by strychnine that 
it loses this property of becoming refractory, it may then discharge 
stimuli continually and excite tonic contractions. 

Still other inhibitions of different kinds are removed by strych- 
nine, — for example, those which normally prevent the stimulation 
of one sensory neuron from spreading at will to other parts by way of 
secondary paths. These secondary paths extend in so many directions 
and are so branching that any particular sensory impulse from any 
sensitive point could probably be carried to all the motor cells in the 
central nervous system. As a rule, however, such impulse passes 
only along the shortest or most open path which runs to the physiologi- 
cally more nearly related motor cells and passes to all others by way 
of these secondary paths only in imperceptible and ineffective inten- 
sity (Exner 3 ). 

Moreover, as a result of Sherrington's fundamentally important 
investigations, it has been shown that normally the excitation of an 
agonist (e.g., flexor muscle) is regularly accompanied by inhibition 
of its antagonist (e.g., the corresponding extensor), and that, there- 
fore, normally, both cannot reflexly be caused to contract. One may 
look upon this as due to the fact that between two antagonistically 
coordinated motor cells there is always a reciprocal inhibitory 
mechanism which so acts, that when a cell (m, Fig. 3) is excited, the 
antagonistic cell (m x ) is automatically inhibited. 

This mechanism is indicated diagrammatically in the figure by 
the two arrows with the minus sign. Normally, the impulse from the 
spinal ganglion reaches in effective strength only the cell m, while 
to m 1 there comes only an inefficient impulse, for the path is not 
opened, or is obstructed by certain obstacles, such as interposed cells, 
which are indicated in the diagram. Therefore, cell m is stimulated, 
while in some way or other m x is inhibited. As a result of the action 
of strychnine, however, the side path to m 1 (as also all other side 
paths) is freed of all obstacles or inhibitory influences, and permits 
the passage of just as much stimulating impulse as does the main 
path running to m. Thus, both cells m and m l receive equally strong 
stimuli, and their reciprocal intracentral inhibitory mechanisms com- 
pensate each other, as it were. As a result agonist and antagonist 
both contract. 

Action in Higher Animals. — The action of strychnine on reflex 
excitability is practically identical in all vertebrates, but in the 



STRYCHNINE 



17 



higher animals there is more evidence of increased sensitiveness of 
the reflexes in the brain, especially of the reflexes resulting from 
stimulation arising in the more highly developed organs of sense. 

In the higher vertebrates the susceptibility to strychnine is much greater 
than in the frog. The lethal dose for the latter is 2 rag. per kilo., while for 
rabbits, dogs, and cats it is from 0.6-0.75 mg. per kilo. On the other hand, 
birds are in the highest degree insusceptible to strychnine administered by 
mouth (Falck). 

After receiving an injection of an effective dose of strychnine, a 
rabbit soon manifests a peculiar uneasiness. He cocks his ears, raises 
his head, etc. Soon, quite suddenly and following any sort of stimula- 




ia. 3. — Diagram of the intracentral inhibitory mechanism of the spinal 



tion, a tonic convulsion occurs, the extremities becoming stiff in a 
position of extension, and the body rigid in a state of opisthotonos. 
The convulsions may last a minute or longer, and during them the 
tremor of the muscles may be felt. 

As all the respiratory muscles take part in the tonic contractions, 
respiration is prevented and the symptoms of asphyxia appear, if the 
convulsion lasts long enough, but, as a rule, the animals do not die 
during the convulsion. More often, after more or less numerous con- 
vulsions a condition of paralysis develops. The reflex excitability 
steadily diminishes, the blood-pressure falls and remains very low, 
and the respirations become constantly weaker until they stop 
entirely. 

In addition to these characteristic actions on the reflex mechanism 
of the cord, in the higher animals strychnine exerts a similar exciting 
action on the reflex centres in the cerebrum and medulla. The 



18 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

blood-pressure rises during the convulsions and the pulse becomes 
slow, even when asphyxia is prevented by artificial respiration. Also 
when the convulsions are prevented by curare, there are periodic 
recurrences of the rise in blood-pressure and of slowing of the pulse 
(S. Mayer) for which the increased excitability of the vasomotor and 
vagus centres is responsible. A similar action on the respiratory 
centre also occurs, for it may be shown experimentally that after 
the excitability of the respiratory centre has been markedly depressed 
by such a drug as morphine, strychnine in doses which are not large 
enough to cause convulsions will bring about a marked increase in 
the excitability of this centre (Biberfeld). 

The action of strychnine on the different special senses is of con- 
siderable therapeutic importance. Touch, smell, and taste all become 
more acute, and the sensitiveness of the visual organs is improved so 
that the field of vision is enlarged and the ability to distinguish colors 
is increased. Filehne has shown that these effects, except those on 
vision, are the results of an action on the central sensory tracts in 
the cerebrum. In the eye the drug acts directly on the retina, which, 
as is well known, may be looked upon as a portion of the cerebrum. 
Inasmuch as this increase in the sharpness of the senses results from 
an action of strychnine on the sensory centres in the brain, the in- 
creased sensibility of the senses appears entirely analogous with the 
increased excitability of the sensory organs in the cord. 

Paralytic Action of Strychnine. — Strychnine, however, exerts 
still other actions on the nervous system. Mammals, as well as frogs, 
die in a state of paralysis which follows the convulsions. This has 
often been explained as due to an exhaustion of the nervous system 
as a result of the convulsions. While it is a fact that an increased 
tendency to exhaustion goes hand in hand with the increased excita- 
bility of the reflex organs, for the unchecked discharge of impulses 
readily leads to an exhaustion of the energy in the receptive organs 
which have no time to rest or to form anew those substances consumed 
by their discharge of energy, still the exhaustion of the cord resulting 
from the convulsions in one way explains the rapid paralysis occurring 
in frogs after large doses of strychnine. Neither does it explain the 
fact that in mammals death results from respiratory and vasomotor 
paralysis, which may occur after only a few convulsions. These 
phenomena result rather from another later action of strychnine, a 
paralyzing one, which is more in evidence, as compared with the 
convulsant action, the larger the amounts of the poison absorbed. 

In such case a general paralysis develops after tetanus of short 
duration. In frogs in which this paralysis is not fatal, a tetanus 



STRYCHNINE 19 

lasting for days may be observed after the paralysis has passed off. 
This paralysis also has nothing to do with that depression of the 
heart which occurs after large toxic doses of strychnine {Igersheimer). 
It is the final cause of death in cases when very large amounts of the 
poison have deen taken (Poulsson) . 

After large doses of strychnine a ''curare" action occurs in the 
frog, which is much better developed in the Rana esculenta than in 
the R. temporaria. 

It is a noteworthy fact that at a time when the reflex excitability 
from tactile skin irritation is highly exaggerated, chemical irritation 
of the skin (by acetic acid) and other painful stimuli (by cutting) 
produce no effect. Moreover, irritation of the viscera, which in 
normal frogs causes defective movements, has no effect in strych- 
ninized ones. It is, therefore, apparent that the different receptive 
systems in the spinal cord are variously affected by this drug. The 
perception of a painful stimuli is from the start diminished as a result 
of a central depressing action. Only for the stimuli through the ordi- 
nary senses does the nervous system become over-excitable (T. Sano). 

Toxicology. — Strychnine poisoning in man occurs usually as a 
result of taking the poison by mistake or as the result of exceeding 
the permissible medicinal dose. The promonitory symptoms are feel- 
ings of drawing and stiffness in certain muscles, hypersusceptibility to 
sensory impressions, restlessness, and trembling. After larger doses 
(more than 0.03 gm.) exaggerated reflex excitability and a marked 
feeling of anxiety develop and suddenly the attacks of general tetanic 
convulsions start. The convulsions may last from several seconds to 
two minutes, and, as during them respiration ceases, death may result 
from asphyxia. In the intervals between the convulsions the con- 
sciousness is maintained, but during the convulsions the increasing 
asphyxia beclouds it. Usually after three or four severe convulsions 
death results from exhaustion of the nervous system (Denys). The 
mean lethal dose for an adult is from 0.1-0.12 gm. 

In the treatment of strychnine poisoning the first aim is to 
prevent the occurrence or to lessen the violence of the convulsions, 
which in themselves jeopardize life. This may be accomplished either 
by i|iiieting the hyperexcitable centres by the administration of 
narcotics or by interfering with the passage of the abnormally violent 
motor stimuli, which may be done by depressing the motor nerve- 
endings with curare. Theoretically the treatment with curare should 
be the more efficient treatment for strychnine poisoning, for, as strych- 
nine itself exerts a paralyzing action on the nervous centres, the ad- 
min ist ration of narcotic drugs increases the danger of the develop- 
ment of such central paralysis. However, as stated in the discussion 



20 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

of curare, it is difficult to determine the dosage of this drug exactly 
enough to secure cessation of the convulsions without also stopping 
the respiration. 

If the convulsions have not already started, chloral should be given 
by mouth or by rectum, or, if nothing else is at hand, alcohol in one 
form or another. All noises, draughts, or sensory stimuli are to be 
avoided, and finally, by apomorphine or by lavage, any unabsorbed 
poison should be removed from the stomach. [Even although the con- 
vulsions have not yet started, the administration of apomorphine 
and the resulting vomiting, or the use of the stomach- tube, is extremely 
liable to start up the convulsions in an unana?sthetized patient, — Tr.] 
If the convulsions have already started, chloroform anaesthesia should 
at once be induced and the stomach emptied by lavage. As the 
chloroform anaesthesia passes off, chloral hydrate should be given by 
rectum and measures taken to stimulate diuresis, in order that the 
strychnine may be excreted while the patient is sleeping under the 
influence of chloral. 

In animal experiments artificial respiration may bring about a 
cessation of the convulsions caused by strychnine. The breathing of 
pure oxygen also moderates or prevents the occurrence of the con- 
vulsions, while an insufficient oxygen supply augments their violence 
{Osterwald) . 

Therapeutic Uses. — Among the therapeutic indications for strych- 
nine is its employment in amblyopias and amauroses without ana- 
tomical change or in incipient optic atrophy, in which conditions its 
curative or helpful action has been certainly demonstrated. More- 
over, in cases of impaired hearing of central origin, improvement has 
been claimed from its use in dosage up to 0.01 gm. per dose ( !) and 
0.02 gm. per diem (!) of strychnine nitrate, subcutaneously injected. 
Its use in motor paralysis is recommended from many sides. 
Novnyn, among others, reports good results in pareses, but never 
in complete paralysis, from the daily injection of 0.01 gm. in 
series of 10-12 injections, with 6-8 days' intervals intervening. It 
would thus appear that this drug favorably influences the re-establish- 
ment of motor functions only when the interruption of the motor tract 
is not a complete one. Strychnine is also used in cases of paralysis 
or weakness of the sphincters and in nocturnal enuresis. 

In atony of the alimentary canal the effect of strychnine is uncer- 
tain. For this indication it may be used in the form of the extract 
1-5 eg. (!) per dose up to 0.1 gm. ( !) per diem. The employment of 
the tincture in various affections of the stomach and intestines rests 
probably upon its action as a bitter. 



STRYCHNINE 21 

The employment of strychnine as an antidote in narcotic pois- 
onings, especially in poisoning with chloral hydrate, alcohol, centrally 
depressing snake-poisons, etc., rests on a better physiological foundation 
than the above-mentioned therapeutic uses. In other countries strych- 
nine is used much oftener for such indications than in Germany, 
where the preference is given to the harmless caffeine. As the 
excretion of strychnine by the kidney takes place extremely slowly 
(Ipsen), it can accumulate in the body when administered for a 
considerable period. 

[That strychnine is of value as a stimulant in various conditions 
of depression of the central nervous system, especially in infectious 
disease, is firmly believed by many physicians, of whom the translator 
is one. That its value is often over-estimated is probably true, but 
the weight of clinical evidence certainly is in favor of its usefulness 
in such indications. Nothing, however, can be expected from small 
doses, such as 1.0 mg. 3 to 6 times a day, which are the usual doses 
given. Doses three or more times as large are, as a rule, the only ones 
capable of producing real benefit. Naturally, when such larger doses 
are given, the patient should be carefully watched, and at the first 
sign of exaggerated reflex excitability the drug should be diminished 
or stopped. In this connection the translator would call attention to 
the antagonistic effects of alcohol and strychnine, which would appear 
to him to indicate that it is irrational, at least in respect to the effects 
on the central nervous system, to give to a patient large doses of both 
of these drugs. — Tr.] 

Brucine, which occurs together with strychnine in nux vomica, 
is chemically closely related to it, being probably dimethyloxystrych- 
nine (J. Tafel), and its physiological action is similar to that of 
strychnine, but much weaker. 

BIBLIOGRAPHY 

'-Baglioni: Zeitschr. f. allg. Phys., 1909, vol. 9, p. 1. 

1 Baglioni: Zeitschr. f. allg. Phys., 1904, vol. 4, p. 113. 

■Baglioni: Zeitschr. f. allg. Phys., 1909, vol. 10, p. 87. 

Biberfeld: PflUger's Arch. f. d. ges. Physiol., 1904, vol. 103, p. 2G6. 

Birge: Dubois' Arch., 1882, p. 481. 

Bongers, J'.: Arch. f. Anat. u. Phys., 1884, p. 331. 

Denys: Arch. f. exp. Path. u. Pharm., 1885, vol. 20. 

u i : Entwurf zu einer Erklarung d. psychischen Erscheinungen, 1S94, p. 59. 
• I ner: Loc. cit., pp. 88, 92 ff. 

Exner: Loc. cit., pp. 58, 59. 
Falck: Zentralblatt f. d. mod. Wiasenschaften, 1899, No. 29. 
Filehne: PflUger's Arch., 1901, 83, with literature, p. 3G9. 
Harnack, E.: Arch. f. exp. Path. u. Pharm., vol. 34, p. 15G. 
Houghton and Muirhead: bled. News, 1895. 
[gersheimer: Arch. f. exp. Path. u. Pharm., 1905, vol. 54. 
Ip-n: Vicrtrlj.ilirschrifl f. gerichtl. Medizin, 1892, vol. 4, p. 15. 
KOIliker: Virchow'a Arch., L856, rol. 10, p. 239. 
Mayer, S.: Ber. d. kais. Akad. d. Wissensch. in Wien, 1872, vol. G4, Part II, 

p. 657. 
M.ycr, 11.: Zeitschr. f. rationelle Medizin, 1840, vol. 5, p. 257. 



22 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Miiller, Johann: Handbuch d. Phys. d. Menschen, 1844, p. 49. 

Naunyn: Ueber subcutane Strvchnineinspritzungen, Ges. Abhandlungen, 1909, 

vol. 2, p. 790. 
Osterwald: Arch. f. exp. Path. u. Pharm., 1900, vol. 44, p. 451. 
Poulsson, E.: Arch. f. exp. Path. u. Pharm., 1889, vol. 26, p. 22 ff. 
Sano, T.: Pfliiger's Arch., 1908, vol. 124. 

Sherrington: Phil. Transact. Rov. Soc., 1898, vol. 190, p. 160. 
Tafel, Jul.: Liebig'a Annalen, 1898, vol. 304, p. 26. 

GENERAL CHARACTERISTICS OF ALKALOIDS 

As has been mentioned, strychnine is a typical alkaloid, and, as 
many of our most important drugs belong in this group, a brief 
description of their general characteristics will be advantageous at 
this time. 

The alkaloids are nitrogenous bases, chiefly of vegetable origin. 
Commonly, however, this term is applied only to those vegetable bases 
which exert powerful physiological actions, although it is also applied 
to certain bases formed by the decomposition of animal tissues, the 
so-called ptomaines, or cadaveric alkaloids. 

Most alkaloids contain C, N, H, and O, but a few contain no O. 
In general they may be considered to be substituted ammonias or 
ammonium bases, the nitrogen in most of them entering into the 
formation of such closed carbon rings as those of pyrrhol, pyridine, 
quinolin, etc. 

As a result of their basic character they, like ammonia, readily 
form salts with acids. These are broken up by ammonia, fixed alka- 
lies, and other bases, in accordance with their mass action and their 
basicity. In this way the insoluble alkaloids may be precipitated from 
aqueous solutions of their salts. 

In contradistinction to the free alkaloids, these salts are, as a rule, 
soluble in water and in alcohol, but are insoluble in benzene, ether, 
chloroform, and amyl alcohol, in which the free alkaloids are more or 
less soluble. The usual methods of isolating alkaloids are based on 
these solubilities and insolubilities. 

After isolation the alkaloids are identified by various methods, 
among which only the color-reactions and physiological tests need 
be mentioned here. As the color-reactions often are ambiguous unless 
the alkaloid is absolutely uncontaminated by other substances, the 
physiological tests are often more positive and more definite than the 
tests based on color-reactions. This is notably the case with strych- 
nine (Rankc). 

Tannic, phosphomolybdic, phosphotungstic, and picric acids form 
with most alkaloids, even when highly diluted, salts which are very 
insoluble in water and which consequently are precipitated. The 
chlorides of platinum and gold and the chlorides and iodides of mer- 
cury, bismuth, and zinc form with the chlorides of most alkaloids 
very insoluble double salts. These reagents may therefore be used 
to determine the presence of alkaloids. 



CONVULSANTS 23 

CONVULSANTS 

Besides the toxic excitation caused by strychnine, the typical con- 
vulsant, there are other types of toxic excitation of the central nervous 
system which may excite convulsions, which, however, are not pre- 
cipitated by sensory stimuli, and hence are not of a reflex character. 
Such convulsions differ from those produced by strychnine in not 
being characterized by a simultaneous contraction of all the muscles 
in the body (including the antagonists), for in them only certain 
groups of muscles contract. As previously stated, in strychnine 
convulsions all the muscles, both agonists and antagonists, contract 
simultaneously, a tetanic or tonic convulsion resulting. This simul- 
taneous contraction of all the muscles finds its explanation, as already 
stated, in the unhindered spreading of the sensory stimulus over all 
the afferent paths and bypaths, this resulting in an equally simul- 
taneous excitation of all the motor centres, even the antagonistic ones. 
On the other hand, certain other convulsant poisons, without inter- 
fering with the inhibition of the antagonists, cause involuntary muscu- 
lar movements similar to those of orderly normal motions. Such con- 
vulsions are known as clonic convulsions, and it is characteristic of 
them that their occurrence is apparently spontaneous although in real- 
ity they are caused by summation of internal stimuli. Like epileptic 
attacks, after a short period they cease for a time, and therefore are 
described as being of a periodic or epileptiform type. 

In contradistinction to the tonic convulsions which are of spinal 
causation, these epileptiform convulsions are excited by conditions 
arising in the higher centres normally controlling voluntary move- 
ments, which in different species of animals are situated in different 
parts of the central nervous system. 

For tli is reason there has arisen much confusion in the statements about 
the seat of action of the so-called convulsants. Prevost and Batelli, by stimulat- 
ing various portions of the central nervous system with a powerful alternating 
current, endeavored to determine the parts of the central nervous system from 
which clonic, and those from which tonic convulsions could be excited. In 
full-grown dogs and cats, these authors found that clonic convulsions resulted 
only when the cortical motor regions were stimulated, while stimulation of the 
centres lower down caused tonic convulsions. On the other hand, stimulation 
of the cerebral cortex in rabbits, guinea-pigs, and new-born dogs and cats was 
Dot followed by clonic convulsions, but these did occur when the medulla of 
t tiese animals was stimulated. Stimulation of the spinal cord may cause clonic con- 
vulsions in frogs, but only tonic contractions in the higher animals ( Samaya) . 

It would, therefore, appear that, in the higher animals, epilepti- 
form CONVULSIONS OF TOXIC ORIGIN ARE DUE CHIEFLY TO THE ACTIONS 
OF VARIOUS POISONS ON THE CEREBRAL CORTEX. It i.S, however, not 

impossible that such poisons may also net on the subcortical centres. 

By certain experiments (Luchsinger) in which transverse section of the 
central nervous system was performed at different levels, it has been demon- 
strated that picrotoxin, a typical convulsant, causes convulsions not only by 
its action on some higher portion of the central nervous system but also by its 
action on centres in the cord. On the other hand, there are other convulsant 



24 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

poisons whose seat of action is sharply limited; for example, the esters of 
morphine-glycocholic acid, which cause violent convulsions. By similar ex- 
periments these convulsions have been shown to he due to an action on certain 
centres in the pons, the other portions of the central nervous system not being 
involved ( Barnes ) . 

The large number of the regions, from which clonic convulsions 
may be excited, sufficiently explains our incomplete knowledge of the 
place and manner of their causation. 

Camphor. — Among the many substances which may cause epilepti- 
form convulsions, camphor should be especially mentioned. In warm- 
blooded animals large doses of this drug cause convulsions with clonic 
movements of the extremities, trismus, and tonic contraction of the 
facial muscles, which, in their periodic character and slight danger 
to life, are typically epileptiform, and are rarely followed by paralysis 
or even marked weakness. The therapeutic action of camphor on the 
central nervous system depends on the fact that doses, too small to 
cause convulsions, stimulate certain vitally important cerebral and 
medullary functions. Other convulsants — e.g., picrotoxin and coria- 
myrtin (from Coriaria myrtifolia) — produce similar effects (Koppen). 

A stimulation of the convulsion centres may also occur as a 
toxic side-action of a number of other much-used drugs. For ex- 
ample, in even slight atropine poisoning a certain degree of motor 
unrest with involuntary movements of the hands and fingers occurs, 
while in severe poisoning there occur outbreaks of clonic convulsive 
movements of the extremities, trismus, and rolling and twisting 
movements, which may continue to recur for hours or for days. In 
cocaine poisoning, too, both epileptiform and tonic convulsions may 
occur. Santonin, so widely used as a vermifuge, is also a typical 
convulsant and has often been responsible for poisoning in which 
epileptiform convulsions occur. 

BIBLIOGRAPHY 
Barnes: Arch. f. exp. Path. u. Pharm., 1901, vol. 46, p. G8. 
Gottlieb: Arch. f. exp. Path. u. Pharm., 1892, vol. 30. 
Koppen: Arch. f. exp. Path. u. Pharm., vol. 29, p. 327. 
Luchsinger: Pniiger's Arch., 1878, vol. 16, p. 532. 

Prevost u. Batelli: Travaux du laborat. de physiol. de Geneve, 1894, vol. 5. 
Ranke: Virchow's Arch., 1879, vol. 75. 
Samaya: Trav. du lab. de physiol. de Geneve, 1903, vol. 4. 

CEREBRAL STIMULANTS 
"Wherever convulsions occur as toxic side effects, this will be 
mentioned in the general discussion of the drug. In this connection 
it should be particularly noted that the higher psychic portions of 
the cerebrum, the centres of conscious perception and for voluntary 
movement, are capable of a stimulation or of an exaltation of their 
excitability similar to that which the convulsive centres manifest in 
more advanced poisoning. The earlier stages of such actions may be 
utilized therapeutically to stimulate cerebral functions when they 



CEREBRAL STIMULANTS 25 

are depressed. The discussion of the action of strychnine on the 
central perception of sensory stimulation has made it clear that 
certain drugs can produce such an exaltation of the excitability of 
such cortical centres. In an analogous fashion, stimulating drugs may 
bring about an improvement of the functions of those other centres 
on the activity of which consciousness depends. At any rate, there 
is at the present time no conclusive evidence which forces us to believe 
that the symptoms of cerebral stimulation are always only a secondary 
result of the depression of higher psychic centres, the inhibitory ones 
in particular. 

The clearest evidence that a direct stimulation of the cerebral func- 
tions may occur is found in the fact that depression of the cerebrum 
may be combated by stimulating substances. In animals conditions 
of cerebral narcosis, such as are produced by alcohol, paraldehyde, or 
chloral, may be interrupted or overcome by the administration of 
stimulating drugs, even after consciousness, voluntary movements, 
and perception of pain are abolished and most of the reflexes, includ- 
ing the corneal, are markedly depressed. 

In dogs, Bint demonstrated the antagonistic action of caffeine and alcohol, 
and llosso, by injections of 0.01-0.02 gm. of cocaine hydrochlorate, was able to 
awaken dogs from the deep sleep produced by chloral. Schmiedeberg "found that 
" rabbits, narcotized by paraldehyde until consciousness was completely abolished, 
could be so thoroughly awakened by injection of % to 1 mg. of picrotoxin, that 
they moved about in quite a lively fashion." Koppen succeeded in doing the 
same with coriamyrtin injected into rabbits narcotized by chloral, and Gottlieb, 
after injecting camphor into rabbits deeply narcotized by paraldehyde, observed 
the return of the reflexes (including the corneal) which had been abolished, the 
animals waking up and moving about voluntarily. This last-cited observation 
illustrates well the reviving action of camphor on the sensorium, which is at 
times observed even after its administration to patients in extremis. 

Therapeutic Indications. — The indications for the administration 
of these stimulants of the central nervous system are found in all 
acute conditions of depression, which are characterized by a failure 
of such vital functions as those of the respiratory and vasomotor 
centres. Such a condition is that of the so-called collapse. The 
stimulating effects of camphor, caffeine, atropine, and other drugs, 
indicated in collapse, are chiefly due to their action on the circulation 
and respiration, and therefore this will be more fully discussed in the 
sections dealing with the pharmacology of those functions. However, 
when they are employed, they also produce a stimulation of the cere- 
bral functions whenever it is still possible to produce any affects 
opposing Hie depression of the central nervous system. 

I" addition to their therapeutic actions, the drugs of this class 
are of importance on account of their extensive consumption in various 
beverages. Especially is litis the case with caffeine, for even the 
small amounts of the drug, which are present in tea, coffee, and some 
other commonly used beverages, produce readily recognizable effects 



26 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

on the normal central nervous system. In animals the toxic action 
of caffeine manifests itself by an exaggeration of the reflexes, especially 
the spinal ones, which is entirely analogous to that produced by strych- 
nine. In man the toxic action manifests itself chiefly by the symptoms 
of its cerebral effects, restlessness and great excitement (Curschmann). 
In susceptible individuals, even small amounts produce the first stages 
of cerebral excitement with an increased reflex excitability. This is 
the reason why many individuals are unable to fall asleep as usual 
after drinking such beverages as tea and coffee. Krapelin's delicate 
psychophysical analysis of the effects of tea shows that these are due 
almost entirely to the caffeine contained in it. Making use of methods 
permitting of exact measurements, he found that tea improves the 
perception of external stimuli and also the association of ideas. This 
confirms the every-day experience that caffeine favors the performance 
of certain cerebral functions and opposes the depressing effects of 
alcohol and of mental fatigue. 

Caffeine is a drug whose action is almost purely stimulating. 
Unlike strychnine, it does not, even in large doses, cause a later stage 
of depression. However, a certain amount of confusion of the cere- 
bral functions does result from poisonous doses, this indicating that 
such doses do exert a certain degree of depressing action of some of 
the brain centres. Of the other cerebral stimulants which are of 
practical importance, camphor is one producing similar effects with 
but slight late depressing action, while most of the other convulsants, 
when given in large doses, cause not only stimulation of certain func- 
tions of the brain but also depression of others, or else a stimulation 
quickly followed by depression. This is the case, for instance, with 
cocaine, so that in poisoning caused by it extreme mental excitement 
and motor restlessness are accompanied by clouding of the conscious- 
ness, while a marked depression of the central nervous system suc- 
ceeds the stage of excitation. With this drug, even in the early stages 
of the action on the central nervous system, there is clear evidence 
of interference with some of the higher brain functions, so the con- 
dition may be spoken of as a cocaine "jag" (Rausch). Only after 
very small doses is its action an almost exclusively stimulating one. 
Such are the doses taken by the natives of South Africa when chewing 
coca leaves, and it is this stimulating action on the cerebrum which 
accounts for this custom. 

BIBLIOGRAPHY 

Binz: Arch. f. exp. Path. u. Pharm., vol. 0, p. 31. 

Curschmann: Deutsche Klinik, 1873, p. 377. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1S92, vol. 30, p. 21, exp. p. 39. 

Kelp: Cited from Binz, Arch. f. exp. Path. u. Pharm., vol. 9, p. 41. 

Ktippen : Arch, f . exp. Path. u. Pharm., vol. 29, p. 327, exp. p. 343. 

Kriipelin: Ueber die Beeinflussung einfacher psychischer Vorgiinge durch einige 

Arzneimittel, Jena. 1892, p. 216. 
Mosso: Arch. f. exp. Path. u. Pharm., 1887, vol. 23. p. 205. 
Schmiedeberg: Grundriss der Pharmakologie, Leipzig, 1906, p. 264. 



ATROPINE, SCOPOLAMINE 27 



DRUGS CAUSING SIMULTANEOUS STIMULATION AND DEPRESSION 
OF THE CENTRAL NERVOUS SYSTEM 

Atropine. — The symptoms produced by atropine are typical of 
such a combination of stimulation and depression occurring side by 
side in the cerebrum. A peculiar psychic confusion, with hallucina- 
tions and deception of the senses, accompanies even slight grades of 
poisoning by this drug, while severely poisoned individuals lose con- 
sciousness during the stage of delirium and convulsions. After the 
stage of excitement passes off, they pass into a half-comatose state, 
and in fatal cases death ensues from the paralysis which then develops. 
With a group of alkaloids closely related to atropine, the central 
action causes, after only a short stage of excitement, a depression of 
the cerebral functions. 

Scopolamine. — This is most pronounced in the case of scopolamine 
(identical with hyoscine), which is widely used as a sedative and hyp- 
notic and which in its peripheral actions closely resembles atropine. 
Its therapeutic usefulness results from its actions on the central ner- 
vous system, which differ from those of atropine in that with scopo- 
lamine a primary depression of certain cerebral centres is more 
prominent than is the case with atropine. Scopolamine may, there- 
fore, be used to induce sleep or at least to produce a sedative effect in 
cases of most pronounced excitement, where other hypnotics (even 
opium) are ineffective. 

Scopolamine is a lsevorotary alkaloid with the formulae d,H 21 N0 4 , which 
occurs in the various solanacese. First discovered in Scopolia atropoides, but 
also present with hyoscyamine in Hyoscyamus niger and Duboisia myropoides, 
and in small amounts also in Atropa belladonna and other related plants. 
Chemically it resembles atropine closely. Scopolamine was formerly named 
hyoscine and was chiefly prepared from Hyoscyamus niger, but later investiga- 
tions have established the identity of hyoscine aud scopolamine (E. Schmidt). 

Scopolamine resembles atropine closely in its peripheral effects on 
the pupils, secretions, etc. Its therapeutic importance is, however, 
due to its central actions, which are distinguished from those of atro- 
pine by a much more prominent primary depression of certain 
cerebral centres. For a long time it has been known that the extract 
made from henbane acted as a sedative, — that is, in a different fashion 
from the atropine and hyoscamine contained in it. Impure prepara- 
tions of hyoscamine, which probably contain scopolamine, have often 
been used with varying success ;is a means of quieting insane patients. 
Pure hyoscine, first isolated by Ladenburg, was a third alkaloid 
obtained from hyoscyamus, and later, whim proved to be identical 
with scopolamine, was introduced into therapeutics by Gnauck and 
others. 



28 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

It has been experimentally demonstrated that scopolamine has scarcely any 
narcotic action in rabbits, but shortly after injection of an effective dose dogs 
fall more or less deeply asleep. Before going to sleep, they manifest a distinct 
restlessness, evidently due to hallucinations and illusions, which is accompanied 
by uncertain gait and staggering, briefly by a tipsy condition, which precedes 
the stage of fatigue and sleepiness. 

Man is, however, more susceptible to the central action of scopola- 
mine, and doses of V^-l 1 /^ mg. are usually enough to produce the 
required sedative effect. [Few would care to give l 1 /-;. mg. ( 1 / 40 gr.) ; 
at any rate, as a first dose. — Tr.] Mydriasis and paralysis of the 
accommodation and dryness in the mouth and throat are accompany- 
ing side effects. The drug is usually used in the form of the hydro- 
bromide and is best administered subcutaneously. 

Although one speaks of scopolamine sleep, and also actually 
can with it induce sleep even in conditions of marked mental excite- 
ment, there is an important difference between the hypnotic action 
of scopolamine and that of the true hypnotics. The primary seat of 
action with scopolamine does not lie in the centres for the perception 
of sensory impressions, by an action on which the true hypnotics 
favor the process of falling asleep, for scopolamine primarily depresses 
the excitability of the motor centres. When the scopolamine action 
commences to develop, the patients show a relaxation of their muscles 
and the motor unrest ceases. Only after this do the patients sink 
down in a relaxed position, the breathing sometimes becoming slightly 
stertorous on account of the relaxation of the epiglottis and the speech 
a little uncertain. At this stage the patients are still conscious and 
are sensible of visual impressions, etc. After this sleep ensues, but 
is often preceded by delusions, hallucinations, and delirium. 

The characteristic relaxation of the muscles observed in the earliest phases 
of the scopolamine action and the efficiency of the drug in combating motor 
excitement are in agreement with Ramm's statement that in dogs this drug 
quickly depresses the cerebral motor centres so that they no longer respond 
to electric .stimulation. 

This drug is also used with benefit in nervous diseases with symp- 
toms of motor irritation, and especially in paralysis agitans. Its use 
as a substitute for atropine in ophthalmologic practice will be dis- 
cussed in another chapter. A better acquaintance with the action of 
morphine is also necessary before the use of scopolamine in combina- 
tion with morphine as a narcotic for surgical procedures and as an 
adjuvant for the general anaesthetics may be discussed. 

The dangers associated with the use of scopolamine lie in an 
extension of its depressing action on the respiratory centre, as also 
in the possibility of cardiac failure. In general, the margin between 
hypnotic and toxic or lethal doses of scopolamine is quite large in 
dogs as well as in man. Dogs, in whom 1 mg. is an efficient dose, 
sometimes may support 1 gramme without fatal effect. However, in 



MORPHINE 29 

man, as also has been observed in a few cases with the dog, the individ- 
ual susceptibility appears to vary greatly. In conditions of pro- 
nounced psychical excitement, not only are larger doses required, but 
also larger doses may be borne without harmful results. 

In the practical employment of scopolamine, the variable 
activity of different preparations has been f ound quite disturbing. 
This is due to the great difficulty of obtaining preparations of scopola- 
mine entirely free from contamination by the other related alkaloids, 
some of which have quite different and in part antagonistic pharmaco- 
logical actions. Thus, Atropa belladonna contains, besides scopola- 
mine, another alkaloid, apo-atropine (apatropine) , which is much less 
powerfully mydriatic but very poisonous, causing pronounced central 
excitation. This alkaloid appears often to be present as a contamina- 
tion in preparations of scopolamine (Robert). According to Kessel, 
it is easy to detect the presence of this contamination by adding 
a few drops of a solution of potassium permanganate to the suspected 
solution, reduction indicating the presence of this particular con- 
tamination. 

BIBLIOGRAPHY 

Erb: Therapeut. Monatshefte, 1887, p. 252. 

Gnauck: Charite-Analen, 1882, vol. 8. 

Kessel : Arch, internat. de Pharmacodynamic et de Ther., 1906, vol. 16. 

Robert: Zeitschrift f. Krankenpflege, 1905, vol. 27, No. 2. 

Robert u. Sohrt: Arch. f. exp. Path. u. Pharm., 1886, vol. 22. 

Koehmann : Arch, internat. de Pharmacodynamic et de Ther., vol. 13, 1903, p. 99 ; 

Therapie der Gegenwart, Mai, 1903. 
Ramm: Inaug.-Diss., Dorpat, 1893. 
Schmidt. E.: Arch, der Pharmacie, 1892 and 1894. 
Wood: Therapeutic Gazette, 1885. 

MORPHIXE GROUP 
Among the manifold forms of cerebral narcosis produced by 
various agents, that produced by morphine is singular in that this 
drug so markedly lessens the sensibility to pain. On the other hand, 
morphine does not depress the excitability of the cerebral cortex in 
anything like the same degree as do the narcotics of the alcohol- 
chloroform group (see p. 43 ff.) , for, long before it completely abolishes 
the cerebral functions, it produces such marked depression in the 
medulla, especially of the respiratory centre, that death ensues before 
reflex excitability of the cord disappears. The effects of morphine 
thus differ from those of alcohol and choloroform in that the different 
portions of the central nervous system are affected by it in a different 
Bequence. With chloroform, alcohol, etc., first the cerebrum, then 
the cord, and last of all the respiratory centres are depressed, while 
with morphine the depression of the respiratory centres occurs simul- 
taneously with [or previously to — Tr.] the depression of the cere- 
liruni, while the reflex excitability of the cord is depressed in a far 
slighter degree. 



30 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

This great sensitiveness to very small doses manifested by certain 
of the functional tracts of the cerebral cortex is of fundamental im- 
portance for the therapeutic usefulness of morphine, for perception 
of pain is diminished by doses which scarcely affect the motor centres 
and which have no appreciable influence on the perception of ordinary 
sensations. Such specificity of action is not shown by the substances 
of the alcohol-chloroform group, for with them such analgesic effects 
are obtained only by doses which also cause sleep. The respiratory 
centre and those closely connected sensory centres which control the 
cough reflex show this same special sensitiveness to morphine. Conse- 
quently, morphine is primarily a pain and a cough reliever, while its 
hypnotic effects are produced only by larger doses. 

Morphine is derived from opium, the inspissated juice of the unripe fruit 
of the poppy, Papaver somniferum. The opium used medicinally comes chiefly 
from Asia Minor and the Balkan peninsula, hut opium is also produced in 
India, China, Persia, and elsewhere. Even the common field poppy contains 
opium, but not in quantities sufficient to justify its commercial preparation 
(Thorns). 

Opium contains a large number of alkaloids, of which about twenty have 
thus far been isolated. However, the main bulk of these alkaloids is made up 
by morphine, and the other alkaloids are either physiologically inert or else 
present in such small quantities that they may be disregarded. Consequently 
the actions of opium are essentially those of morphine slightly modified by the 
other alkaloids present. The usual morphine content of opium is about 10 
per cent., but occasionally rises to as high as 20 per cent. 

Of the other alkaloids, amounting to about 5 per cent, in all, the greater 
portion, about 4 per cent., is the inert narcotine. Papaverine, weakly narcotic, 
codeine, and thebaine, closely resembling strychnine, are present in only minute 
amounts. In opium these alkaloids are combined with meconic acid and are 
accompanied by resinous substances. 

Morphine is present in all portions of the poppy plant, but as the heads 
ripen the morphine disappears and the seeds contain no morphine. 

Morphine, with the empiric formula Ci 7 Hi 9 NO,„ is the first alkaloid which was 
prepared in pure form (Sertiirner, 1804-16), and is a monovalent tertiary base. 
While its constitution has not been definitely established, the last few years have 
nearly solved this problem, and the morphine alkaloids are assumed to be 
derivatives of a hydrated phenanthrene nucleus which contains one alcohol and 
one phenol hydroxyl radical with the third oxygen in special bridge-like 
combination. 




H 'k. 



OH 
H 



H 2 

H 
OH 



H 2 

3, 6 Dioxy 5, 6, 7, 
Phenanthrene. 8 ' Vdr?™" CH 3 ~N UM 2 

phenanthrene. 

Morphine (?). 




MORPHINE 31 

In codeine the alcoholic hydroxyl is methylated, and in thebaine 
both hydroxyls are methylated. 

Free morphine is but slightly soluble in water, more so in alcohol, acetic 
ether, chloroform, and amyl alcohol. Its salts are readily soluble in water 
and readily crystallizable, the hydrochlorate and sulphate being the ones most 
used. The addition of ammonia or of the caustic alkalies to solutions of its 
salts precipitates the free base, which is redissolved by an excess of NaOH or 
KOH. It is readily oxidized by oxidizing agents. 

In vertebrates the susceptibility to morphine increases with the 
higher development of the central nervous system. In order to 
produce distinct effects in a frog of 30 gm. weight, doses must be 
administered which would seriously poison adult human beings. Ob- 
servations on the frog show that the action of this drug is most 
pronounced in those functional tracts which are most highly developed 
and which ontogentically are last to develop. 

Effects on the Frog. — If 0.03-0.05 gm. of morphine hydro- 
chlorate be injected into a frog, the first effect noted is the cessation 
of spontaneous movements. The frog no longer seeks to escape, 
although when stimulated he can carry out well-coordinated and 
powerful movements, at this stage behaving as if decerebrated. Next 
disturbances in the coordination of complex movements develop. The 
frog no longer sits in the normal position, and jumps clumsily, be- 
having as if the corpora quadrigemina had been removed. As the 
toxic action develops still further, the frog is no longer able to leap, 
although still able to turn over when placed on its back, but only 
slowly and helplessly, as after removal of the cerebellum. Finally, 
when laid on the back, it can no longer turn over, respiration ceases, and 
the cranial nerve reflexes {e.g., corneal reflex) disappear, although the 
spinal reflexes persist. At this stage the condition is similar to that 
of a frog after the medulla has been removed. Finally, the spinal 
reflexes also disappear. In the first stage of the action of morphine, 
the depression affects different parts of the central nervous system 
successively, commencing with the cerebrum, much as occurs when 
different portions of the central nervous system are removed in regular 
order (Witkowski). Naturally, the elimination of the different func- 
tion;]] tracts does not take place so precisely under the influence of 
the drug as after operative removal, for the narcotic action in one 
pari of the brain commences before it has been completely developed 
in another portion. This characteristic starting of the depressant 
action, firsl in 11m highest centres and later in the lower ones, occurs 
also in the higher animals. 

The second stage of morphine action, the stage of tetanus, on the 
contrary, can he observed in its lull development only in the cold- 
blooded animals, which, on account of their slight need of oxygen, 
can survive the cessation of the respiration. The increased reflex 
excitability first manifests itself in the frog by so-called spasmodic 



32 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

respiration, groups of deep and rapid respirations being separated 
by long pauses. The spinal reflex excitability, which in the narcotic 
stage was so depressed and later paralyzed, returns again and is 
increased to such a degree that tactile stimuli excite tonic convulsions, 
just as is the case after strychnine. In principle, this second tetanic 
stage is indicated to some extent throughout the animal kingdom, 
but the higher the development of the central nervous system the 
more does this tetanic action fall in the background. If, however, 
dogs which have received large doses of morphine are kept alive by 
artificial respiration, a markedly increased reflex excitability of the 
cord can develop (Lenhartz). In man, too, abnormal reflex excitability 
may be observed after small doses, and in poisoning, especially in 
children, convulsions may occur. On the other hand, in the lower 
vertebrates the narcotic action is far less evident, morphine acting in 
fishes purely as an excitant like strychnine, without producing any 
preliminary depressing action. 

In the more highly developed animals, the development of the 
morphine action does not take place so diagrammatically as in the 
frog. Above all, among the different species, there are not only dif- 
ferences in susceptibility to the drug, but also qualitative differences 
in the reaction of the nervous system to morphine. After adminis- 
tration of this drug to dogs, almost always salivation, retching, vomit- 
ing, and defecation occur. After some restlessness at the start, a 
quieting effect is noted, and then the animals sleep for hours. "When 
large doses have been administered, increased reflexes and twitching 
of the muscles may be noted. "With rabbits, rats, mice, and birds, 
narcosis is induced, but with cats, horses, and cattle, the drug causes 
great restlessness and a tendency to motor activity, with staggering 
and convulsions, but never a true narcosis (Frohner, Hess). Con- 
traction of the pupils occurs, as a rule, in those species which are 
narcotized by the drug, and dilatation in those which are excited. 

This difference in the reaction to morphine, observed in different 
animal species, is of interest because in certain especially predisposed 
human beings morphine may excite instead of quieting the cerebral 
functions. In most human beings, however, a general sedative effect 
and desire for sleep result from doses of from 0.01 to 0.02 gm., while, 
after toxic doses, drowsiness and sleep are gradually succeeded by a 
state of profound unconsciousness. 

The most important action of small doses of morphine is the de- 
pression op the ability to perceive pain. In the dog there results 
a stage of stupor and unwillingness to move, and the power of pain 
perception is almost entirely lost, although the ordinary sensory per- 
ception is hardly affected, nor is there any tendency to fall asleep. 
The motor regions of the cortex remain excitable even in deep narcosis. 
Hitzig observed no diminution of their susceptibility to electric stimu- 
lation, even after large doses. In fact, with moderate doses such 



MORPHINE 33 

stimulation was more regularly followed by a motor effect than under 
normal conditions, although painful procedures {e.g., twisting the 
dura) no longer caused whining or struggling, although the corneal 
and other reflexes were still present. 

In man also the perception of pain is depressed long before the 
sensorium is affected. Formerly it was believed that this was due 
to a peripheral action of morphine on the peripheral sensory organs, 
but careful investigation of the condition of the algesic and the tactile 
senses has shown that morphine causes no diminution of the sensibility 
of the peripheral sensory organs, for the site of injection is no less 
sensitive than the corresponding part on the other side of the body 
{Jolly u. Hilsmann). We are dealing, therefore, with a central 
hypalgesia. 

YVlTH NO OTHER DRUG CAN SUCH AN ISOLATED ACTION ON THE PAIN- 
TERCEIVING CENTRES BE SECURED, ALTHOUGH A SOMEWHAT SIMILAR 
EFFECT, BUT A SLIGHTER ONE, IS PRODUCED BY DRUGS OF THE ANTIPYRINE 
GROUP. 

Doses as small as 5 mg. of morphine hydrochloride are sufficient 
to lessen perception of pain in adult patients who have not become 
accustomed to the drug. On the other hand, 0.01 gm. is not enough 
to produce an hypnotic effect in all individuals. Ordinary disagree- 
able sensations, as those of fatigue, hunger, or discomfort, as well 
as pain, are relieved by morphine, euphoria resulting, and herein lies 
the great danger of habituation to its use. A closer psychophysical 
analysis of these phenomena has demonstrated that the perception of 
stimuli from without is not at all depressed by small doses of morphine, 
but is, on the contrary, distinctly favored {Kr'dpelin). This stimu- 
lation of certain mental processes, which in normal individuals reaches 
its full development about half an hour after administration of 
0.03 gm. of morphine, explains the ability of morphine habitues to do 
hard mental work so long as the morphine is acting. Other psychical 
processes, in which the accomplishment of a motor reaction plays a 
prominent part, as, for example, the performance of a muscular 
reaction after a given stimulation, are from the start retarded by 
morphine. Tins interference with motor processes is responsible for 
the quietness which develops after morphine long before somnolence 
does, and also for the tendency to dream peacefully and quietly, which 
is so characteristic of opium intoxication and which contrasts so 
strongly with the condition produced by alcohol. 

Resides the above-mentioned depression of the central perception 
<>!' pain which is the chief indication for the use of morphine, this 
drug exerts a similar elective action on the respiratory centre, 
tin- expirations being rendered quieter, deeper, and slower by small 
doses. This will be more fully discussed later (p. 337 ff.). 

The quieting effect exerted by morphine on intestinal peristalsis, 
which occurs when the drug is used for relief of pain or cough, may 



34 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

be considered as a side action in so far as it is an undesired one, 
leading to constipation. 

A number of other side actions may be considered from a common 
point of view, as they depend on the depression of certain central 
inhibitions which lessen the tone of the ocnlomotorius and the vagus 
centres, which inhibitions are in part removed by the action of mor- 
phine just as is the case during normal sleep. 

Among these are the contraction of the pupil and the narrowing 
of the cleft between the lids (compare section on pharmacology of 
the eyes) and the increased tone of the vagus centre which causes slow- 
ing of the heart, which, however, occurs only after unusually large 
doses. Of similar origin is the spasmodic contraction of the bladder 
sphincter, which is in part the result of a central interference with its 
sympathetic nervous inhibition and which in human beings may 
prevent micturition in spite of a strong desire. In guinea-pigs this 
particular effect may be so pronounced that at times rupture of the 
bladder and death ensue (Tappeiner) . 

The narrowing of the pupil is of diagnostic importance. It is 
certainly not the result of a local action, for it does not result when a 
morphine solution is dropped into the eye. This myosis is, however, 
characteristic only of the narcotic stage, and is succeeded by dilatation 
when the tetanic stage develops. As above mentioned, it does not 
occur in those animals whose higher centres are excited by morphine, 
for in them the pupils are dilated. Finally, in the last stages of 
morphine poisoning, the asphyxia causes mydriasis. It follows, there- 
fore, that, although the pupils are usually contracted when morphine 
has been taken, the absence of this symptom in no way excludes 
morphine poisoning. 

After small doses vomiting seldom occurs, and then only in espe- 
cially susceptible individuals, and small doses of atropine (0.2 mg.), 
as a rule, will prevent it entirely. After large doses nausea and vomit- 
ing are very commonly the initial symptoms of the poisoning. 

The circulation is, generally speaking, but slightly affected by 
morphine. In man a passing acceleration of the pulse is followed by 
moderate retardation. In the dog, on the other hand, the slowing 
of the pulse is very pronounced and is due to augmentation of the 
central vagus tone. In other particulars in morphine poisoning the 
circulation suffers only secondarily as a result of a depression of the 
heart from the asphyxia and of a paralysis of the vasomotor centres. 
On the other hand, the depression of the respiration is very pronounced 
from the start and colors the whole picture. 

Acute Morphine Poisoning. — Toxic doses range from 0.03-0.05 
gm. of morphine hydrochlorate, 0.2 gm. being the minimum lethal 
dose for adults, while 0.3-0.4 gm. may be considered as the average 
lethal dose for individuals unaccustomed to its use. Poisoning is 
usually the result of taking the drug by mistake or of errors in pre- 



MORPHINE 35 

scribing or compounding or when the drug is taken with suicidal 
intent. Three-quarters of all the cases of morphine or opium poison- 
ing occur in children under five years of age, which fact is explained 
by the great susceptibility of children to this drug. In small children 
even the administration of decoctions of dried unripe poppy heads as 
soothing potions may cause poisoning. Furthermore, inasmuch as 
morphine is excreted in the milk, poisoning of nursing infants may 
result from the consumption of morphine by the wet-nurse. On the 
other hand, the fcetus in utero is very resistant to morphine, as it 
does not breathe on its own account, and consequently the administra- 
tion of this drug during pregnancy carries little risk, except that, 
when administered shortly before delivery, it may jeopardize respira- 
tion of the child after birth. 

In morphine poisoning a condition of deep coma developing in the 
course of 15-30 minutes is characteristic. Large doses cause a deep 
sleep which at the start may be effectively combated by the application 
of external stimuli, but gradually the tendency to sleep is irresistible, 
and the patient passes into a condition of coma in which his response 
to sensory stimulation progressively becomes more faulty and finally 
complete unconsciousness and deep coma develop. The respiration 
gradually becomes more and more infrequent, irregular, interrupted, 
and rattling, and the skin becomes pale and cold, and the face cya- 
notic, but the pulse continues of good force for a long time. Finally 
all reflexes disappear, the infrequent respirations grow progressively 
more shallow, outspoken Cheyne-Stokes respiration often occurring, 
and death occurs as a result of the cessation of breathing, and, as 
the vasomotor centres also are paralyzed, the blood-pressure and the 
temperature of the body fall markedly. As a rule, the pupils remain 
contracted to the end, while sometimes death is preceded by convul- 
sions. In less severe cases the coma may pass off, but often the 
patients, after a temporary improvement, sink back again into a 
comatose condition. When recovery occurs, constipation and diffi- 
culty in urination persist for some time after the patient has recov- 
ered from the deep sleep, which may last for a day or longer. 

Treatment. — In connection with the treatment of acute morphine 
poisoning it is especially important to remember that, although vomit- 
in g ;il most always occurs spontaneously before the coma develops, the 
excitability of the vomiting centre is so rapidly depressed as the 
narcosis develops that emetics cannot cause vomiting. Consequently, 
in cases of poisoning by morphine or opium, it is essential that stom- 
Bch l;ivage be practised for the purpose of removing any of the poison 
not yet absorbed. Inasmuch as morphine after absorption from the 
stomach, or when administered subcutaneously, is excreted again into 
the stomach, morphine may be found there even 15 or 18 hours after 
its administration, and therefore lavage should lie practised even 
many hours after Ihe administration of the drug. This holds good 



36 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

also for eases in which the drug has been administered subcutaneously. 
As the drug is also excreted into the intestine, the attempt should be 
made to empty the bowels by cathartics and enemata. Attempts to 
render unabsorbed portions of the morphine insoluble by administer- 
ing tannic acid produce but slight effects. On the other hand, it is 
possible to destroy morphine in the stomach by lavage with 0.4 per 
mille solution of potassium permanganate or by the administration of 
about 0.1 gm. of this salt. 

In addition to these measures, the treatment is symptomatic, hav- 
ing as its objects the prevention of the deepening of the comatose 
condition and above all the prevention of the threatening cessation of 
respiration. For this reason the attempt is made to keep the patient 
awake until the sleep becomes so deep as to render this impossible. 
For this purpose one leads him about, applies various stimuli to the 
skin, and administers drugs which stimulate the central nervous sys- 
tem, such as camphor, black coffee, etc. If, in spite of such effects, 
the coma deepens, subcutaneous injections are made of atropine, our 
most powerful chemical stimulant for the respiratory centre. This 
antidotal treatment has proved itself to be life saving in many 
cases of poisoning in human beings, if the dosage of atropine is cor- 
rectly determined, and similar results have been obtained in experi- 
ments on animals. The maximum dose should be injected and 
frequently repeated, the behavior of the respiration serving as a guide. 

Therapeutic Uses. — As a means of relieving pain morphine can 
be replaced by no other drug. The ordinary dosage ranges from 
0.003-0.03 gm. per dose, 0.1 gm. per day being the maximal dose 
under ordinary conditions. The detailed discussion of its field of 
usefulness in various internal and surgical diseases, especially in the 
treatment of different types of colic, neuralgias, etc., belongs to the 
clinician. No physician would be willing to do without this most 
valuable of all means of giving relief in painful conditions of an 
acute nature, or in those hopeless chronic cases in whom even the 
danger of acquiring the morphine habit must be looked upon as the 
lesser evil. As is well known, however, this danger must never be 
forgotten, for, in addition to blunting the perception of pain, mor- 
phine produces a condition of euphoria which carries with it the 
temptation to a chronic abuse of the drug even after the original 
occasion for its use has disappeared. The subcutaneous injection 
(introduced in 1855 by the American, "Wood) of from y 2t to 1 c.c. 
of a 1 to 2 per cent, solution is the best means of securing rapid 
relief of pain. Frequently about 0.2 mg. of atropine sulphate is 
added to such injections. It should be remembered, however, that it 
is particularly this form of administering morphine which opens the 
path, to the development of morphine habituation, and consequently 
it is most necessary that the physician should exercise caution in thus 
administering the drug. 



MORPHINE 37 

Another indication for the use of morphine is for the relief of a 
cough or of cardiac dyspnoea. The significance and importance of 
this sedative action on the respiratory centre will be further discussed 
in another connection (see p. 337). 

In the treatment of sleeplessness morphine is not so valuable as 
the hypnotics of the alcohol group in all those cases in which sleep is 
prevented by psychic excitement or nervous restlessness. Morphine 
should be used as an hypnotic only when pain, coughing, or dyspnoea 
prevents the falling asleep. Somewhat larger doses of morphine may 
be used, however, for the relief of conditions of motor excitement in 
the insane and in cases of poisoning by substances which cause cerebral 
excitement. Among such delirium tremens and poisoning by atropine 
are especially to be mentioned. 

Opium. — Where it is desirable to have the effects of morphine 
develop somewhat more slowly or where the local effect on the alimen- 
tary canal is the desideratum, it is the general rule to make use of the 
galenic preparations. Opium itself, containing from 12 to 12% per 
cent, of morphine, is used in dosage of from 0.02 to 0.1 gm., 0.15 and 
0.5 gm. being the maximal single and 24-hour doses. The extracts 
containing 20 per cent, of morphine are to be used in somewhat smaller 
doses. Dover's powder (opium 1, ipecac 1, sugar of milk 8), the tinc- 
ture, and the deodorized tincture, each containing 10 per cent, of 
opium, and the camphorated tincture, containing .4 per cent, of opium, 
are the more commonly used preparations. 

The other alkaloids present in opium (see p. 30) have been 
but little investigated, particularly in respect to their actions in 
man. Narcotine, which after morphine is the one present in largest 
quantities, certainly has little pharmacological action, while the others, 
which are present in smaller quantities, all show a far weaker narcotic 
action than morphine. On the other hand, they all exert a much more 
pronounced stimulating action on the spinal cord, so that many of 
them, when given in toxic doses, produce convulsions of spinal origin 
which are not preceded by any narcotic action on the cerebrum similar 
to that produced by morphine (v. Schroder). The respiratory centre 
Is also stimulated by some of these alkaloids. Consequently the mix- 
ture of all of the opium alkaloids produces a weaker narcotic action 
;ijhI less sedative effects on the respiratory centre than the morphine 
contained in it when given by itself (Wcrthcimer-Raffaloivich, Lowi, 
Bergien). Clinical experience on human beings appears, however, to 
indicate that the mixture of all the opium alkaloids is as efficient for 
thi- relief' of pain as is pure morphine in corresponding amounts. 

Sahli has recently recommended, under the name of pantopon, a 
mixture of the hydrochlorates of all the opium alkaloids, which is 
Boluble in water, claiming that with it one can obtain the effects of 
morphine modified by the actions of these other alkaloids. It is 
essentially a preparation of opium from which the useless constituents 



38 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

have been removed and which may be injected subcutaneously. It 
contains the same alkaloids in the same relative proportions as does 
opium, but in about fivefold concentration, so that 0.02 gm. of pan- 
topon corresponds to about 0.1 gm. morphine hydrochlorate. 

Codeine. — If in morphine the hydrogen of the alcohol hydroxyl 
group is replaced by alkyl radicals, the so-called codeines are obtained. 
The most important of these, the methyl ester of morphine, codeine 
itself, is present in opium in the small proportion of about 0.1 per 
cent. Under the trade names of clionin and peronin, the methyl ester 
and benzoyl ester have been introduced into use. The codeines differ 
from morphine principally in the fact that the action on the respira- 
tory centre persists while the narcotic action on the higher cerebral 
centres is markedly diminished. According to v. Schroder, the 
power of increasing the reflex excitability of the cord is increased. 
These drugs are valuable substitutes for morphine in the treatment 
of coughs. 

In the last few decades codeine has acquired a constantly increas- 
ing importance in the treatment of coughs. It is now manufactured 
synthetically from morphine, and is consequently much cheaper than 
when it had to be prepared from opium. It occurs in the form of 
colorless crystals, soluble with difficulty in water, and forming readily 
crystallizable salts, of which the readily soluble phosphate is the best 
for therapeutical use. 

In man, 0.03-0.06 gm. of codeine produces about the same effects 
in relieving cough as 0.005-0.01 gm. of morphine, while it is about 
20 times less poisonous. Therapeutic doses also produce some quieting 
effect, but even large doses do not cause actual narcosis. On the 
contrary, in the relatively rare cases of idiosyncrasy only restlessness 
and slight muscle twitchings and mydriasis have been observed. In 
animal experiments the narcotic actions on the cerebrum are so slightly 
expressed that the older investigators overlooked them when moderate 
doses were administered, while after larger doses its property of caus- 
ing tetanus is alone evident. 

Codeine, therefore, may be looked upon as a very mildly acting 
morphine. By its use in place of morphine the danger of the develop- 
ment of the habit may be avoided in cases of chronic coughs. It 
appears to be less suitable as a means of relieving pain or as a 
general sedative, and should be used for such purposes as a substitute 
for morphine only in children. 

The ethyl ester of morphine, dionin, closely resembles codeine. 
On the other hand, diacetyl morphine, obtained by the substitution 
of acetic acid radicals for the hydrogen of both of the hydroxyl groups 
of morphine, and known as heroin, possesses a far more powerful 
pharmacological action. Even in doses of a few milligrammes it exerts 
a sedative action on the respiratory centre, but in laboratory experi- 
ments even comparatively small doses produce dangerous toxic effects 



MORPHINISM 39 

on the medullary centres. The dose of dionin ranges from 0.03-0.05 
gm. per dose and that of heroin from 0.003-0.005 gm. ( !) per dose. 
In judging of the value of these substitutes for morphine, the most 
important point to determine is the degree in which they may cause 
habituation similar to that caused by morphine. 

VjMorphinism. — This brings us to a discussion of the most serious 
harmful effect of morphine and opium, the development of chronic 
morphinismus when the drug is continually administered. When 
morphine is chronically misused, it is taken not only for the purpose 
of relieving pain or coughs, but the patient takes it just as soon as 
he feels tired or uncomfortable, and, when it is thus repeatedly taken, 
habituation gradually develops so that the dose must be increased 
in order to obtain the same effects. If the habit has thus been acquired, 
as soon as there is an interruption of its regular administration 
"abstinence" symptoms develop, and the patient suffers from a 
general feeling of distress and becomes restless and consequently has 
recourse all the oftener to the drug in order that he may again be 
quieted and able to perform mental tasks. The rapidity with which 
the dose must be increased varies in different individuals, and the 
daily consumption of one or two grammes of morphine by a morphin- 
ist or even as much as four grammes is no great rarity. Sooner or 
later, depending on the individual resistance, the consumption of such 
amounts leads to* serious psychical disorders and to disturbances 
in the functions of all the organs. The skin becomes dry and rough, 
but at times there is a tendency to profuse sweating. The digestive 
apparatus in particular suffers seriously, catarrh of the stomach and 
intestines, constipation, diarrhoea, etc., developing. Emaciation and 
anoemia, often accompanied by albuminuria and glycosuria, are among 
the other harmful effects- of this habit. When the attempt is made to 
withdraw the drug, severe "abstinence " symptoms appear, and the 
patient suffers from restlessness and sleeplessness, from depression 
accompanied by a feeling of anxiety, or he may become extremely 
excited, or nausea and diarrhoea or even collapse may complicate the 
picture. 

It is the euphoria which accompanies the therapeutic effects of 
morphine which makes it so easy to acquire the habit. Consequently 
the danger is not so great when those substitutes for morphine are 
used in which the specific effect on the cerebrum is less well developed, 
for then there is no such temptation to increase the dose over that 
which produces the desired therapeutic effects. As codeine and dionin 
do not produce any euphoria, their use is not followed by their abuse, 
but, when heroin has been used repeatedly, serious habituation has 
1 □ observed to result. 

Causes op Tolerance to Morphine. — The partial explanation of 
the true cause of habituation — i.e., an explanation of the reason why 
it is necessary constantly to increase the dose in order to obtain the 



40 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

usual effects — has been furnished by the investigations of Faust, 
who found that this is closely related with the fate in the body of 
morphine and its congeners. 

Formerly much care was taken to isolate morphine in unchanged, 
or more or less altered, form from the urine, but small amounts of 
the unchanged alkaloid may be found in the urine only when very 
large doses have been taken, and even altered morphine cannot be 
detected after any usual doses. On the other hand, Mamie found in 
dogs, and later Alt found in human beings, that morphine injected 
subcutaneously was excreted unchanged into the stomach. This ex- 
cretion begins a few minutes after the injection and persists as long 
as do the effects of the morphine. Using more exact quantitative 
methods, Tauber found in the fasces about 41 per cent, of the mor- 
phine which had been injected in the course of 10 days. 

The condition of the mucous membranes of the alimentary canal exerts 
considerable inliuence on the excretion of morphine, hyperemia and increased 
secretion of the epithelium favoring it. By the local action of alcohol or of 
the irritating decoctions of soap bark or of senega root on the alimentary 
canal, McCrudden was able to increase the amount of morphine excreted in the 
faces from 44-47 per cent, to 58-64 per cent, of the amount which had been 
subcutaneously injected each day. His results suggest that in morphine poison- 
ing the elimination of the drug could be favored by the administration of such 
drugs, just as the attempt is made, by increasing the diuresis, to influence 
the elimination of those poisons which are excreted in the urine. 

In Faust's investigation of the causes of habituation, he was able to 
demonstrate that, when a single injection of morphine is given, dogs excrete, 
through the stomach and intestines, about 70 per cent, of the amount adminis- 
tered; he also found that, when each day progressively larger doses are injected, 
the amount of morphine excreted in the freces decreases, so that finally, in spite 
of the daily injection of ordinarily lethal doses, no morphine appears in the 
excretions. Inasmuch as after death the organs of these animals contain 
only very small quantities of the poison, Faust was justified in concluding that, 
when habituated to morphine, the organism acquires the power of destroying 
much larger amounts of this drug than an individual not accustomed to its use. 
On the other hand, according to Bouma, when codeine is repeatedly administered, 
there develops neither any pronounced insusceptibility to increasing doses nor 
any increased power of destroying the drug. 

The results of these investigations have thus made clear one of 
the causes of tolerance, but it is not probable that this is the essential 
and most important cause for the insusceptibility of the morphinist. 
Such individuals exhibit their insusceptibility to large doses of mor- 
phine especially when these are administered subcutaneously, — that 
is, in a manner which favors the very rapid absorption and the rapid 
arrival of the morphine in the central nervous system. In order to 
explain, by an exaggerated or increased power of destruction, the 
tolerance to such amounts of poison as circulate around in the body 
in the first short period following its injection, it would be necessary 
to assume that the poison is very rapidly destroyed. The experiments 
of Rilbsamen with rats habituated to morphine have furnished the 
necessary data to determine this point. He was able to render these 



MORPHINISM 41 

animals tolerant to doses twice as large as the usual lethal dose. 
"When he determined how much morphine was still present in the 
body of such immunized animals at a time when symptoms of the 
poisoning would be at their height in unhabituated rats, he found 
that it was still possible to isolate from the body an amount of the 
unchanged poison which would have produced severe symptoms of 
poisoning in animals which had not been habituated to this drug. 
The animals which had previously received numerous injections of 
morphine, however, showed hardly any symptoms worth mentioning. 

From these findings the conclusion must be drawn that the repeated 
administration of morphine results in the development of a lessened 
susceptibility on the part of the cells. Against this conclusion only 
one criticism may be urged, — namely, that it is possible that the cen- 
tral nervous system acquires in a particularly high degree an in- 
creased power of destroying morphine so that it is not possible for the 
poison to reach the particularly susceptible nervous elements in a 
sufficiently high concentration. Special experiments, not yet pub- 
lished, which were undertaken to investigate this point have failed 
to give any evidence that the brains of immunized animals exhibit 
any such increased power of destroying morphine. 

However, there is an undeniable connection between habituation 
to and the more rapid destruction of certain poisons in the organism 
which has become insusceptible to their toxic actions. In the case 
of certain other drugs such a connection can be demonstrated (Flury). 
Thus, Pringsheim has shown that alcohol when administered daily is 
combusted more rapidly than when given but once. However, in the 
case of alcohol there is no doubt that a diminished cellular suscepti- 
bility develops, for, as is well known, the alcoholic exhibits an in- 
creased resistance to the action of ether, which in its pharmacological 
actions closely resembles alcohol, in spite of the fact that ether is not 
at all combusted in the organism but is excreted unchanged. 

Opiophagia, or opium eating, is quite analogous to morphinism. The ahuse 
of this drug has spread from India over the whole of Asia and Turkey, — in 
and in Turkey, in tin' form of opium eating, in China and in all lands 
whither tin- Chinese have immigrated, in the form of opium smoking. In this 
latter form of indulgence, for which in China opium extracts prepared in a 
special manner are used, undoubtedly a portion of the morphine passes over into 
smoke, but a large portion is destroyed, and consequently the harmful effects 
of opimn smoking do not develop so rapidly as in opium eating. In both cases, 
however, in the course of time the symptoms of a chronic intoxication develop 
Which closely resemble those of morphine (v. Bibra) . 

IIasiiiscii. — In former times various hemp preparations were widely used 
M substitutes for morphine. Under tin' name of hashisch. extracts of the resin 
of Indian hemp, Cannabis Indica, are used as a stimulant throughout the Orient, 
especially in Egypt am! in India as also in Turkey. The great instability of 
its active principle, which has recently been isolated "in pure form by 8. FranJcel, 
'"•.phi ins why various personal experiments which have been made in Europe 

have not always given such typical results as would be expected, judging 

by the descriptions of hashisch intoxication in the Oriental. The condition of 
intoxication produced by hashisch differs from that resulting from the action 



42 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

of morphine in the predominance of pleasant hallucinations and active motor 
restlessness. In experiments on animals, on the other hand, Frankcl found that 
the cannabinol caused only narcosis and a condition of catalepsy. 

Morphine and Scopolamine. — The exaggeration of the effects of 
small doses of morphine which result from its combination with 
scopolamine are of great practical importance. This synergism may 
be experimentally demonstrated in various species of animals, espe- 
cially in those species in which scopolamine alone, even when given 
in large amounts, produces no narcotic effects. The combined adminis- 
tration of small doses of morphine and small doses of scopolamine, 
which by themselves produce hardly any effects, results essentially in 
an exaggeration of the effects of the morphine (Bilrgi, Modelling). 
Morphine and the hypnotics of the alcohol group when administered 
simultaneously also act synergistically, with a resulting exaggeration 
of each other's pharmacological actions {Bilrgi, Fiihner). 

BIBLIOGRAPHY 

Alt: Berl. klin. Woch., 1889, No. 25. 

Bergien, W. : Munchener med. Woch., 1910, No. 46. 

v. Bibra: Die narkotischen Genussmittel u. d. Mensch., Niirnberg, 1855. 

Bouma: Arch. f. exp. Path. u. Pharm., 1903, vol. 50, p. 353. 

Biirgi: Deutsche med. Woch., 1910, No. 1. 

Faust: Arch. f. exp. Path. u. Pharm., 1908, vol. 44, p. 217. 

Flury: Arch. f. exp. Path. u. Pharm., 1910, vol. 64, p. 105. 

Hess: Arch. f. wissenschaftl. u. prakt. Tierheilkunde, 1901, vol. 27. 

Hilsmann: Dissertation, Strassburg, 1874. 

Hitzig: Reicherts u. Du Bois' Arch. f. Anat. u. Phys., 1873. 

Kriipelin: Ueber die Beeinflussung einfacher psychischer Vorgange durch einige 

Arzneimittel, Jena, 1892, p. 225. 
Lenhartz: Arch. f. exp. Path. u. Pharm., 1887, vol. 22. 
Lovvi, A.: Munchener med. Woch., 1910, No. 46. 
Madelung: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 409. 
Mamie: Deutsche med. Woch., 1883, No. 14. 
McCrudden: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 374. 
Pringsheim: Biochem. Zeitschr., 1900, vol. 12, p. 143. 
Riibsamen: Arch. f. exp. Path. u. Pharm., 1908, vol. 59, p. 227. 
Sahli, H. : Therapeutische Monatshefte, 1909, January; Munch, med. Woch., 1910, 

No. 25. 
v. Schroder: Arch. f. exp. Path. u. Pharm., 1883, vol. 17. 
Tappeiner: Sitzungsbericht d. Ges. f. Morph. u. Phvsiol., Munich, 1899. 
Tauber: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 336. 
Wertheimer-Raffalowich : Deutsche medizinische Wochenschrift, 1910, No. 17. 
Witkowski: Arch. f. exper. Path. u. Pharm., 1877, vol. 7. 

ALCOHOL 

The drugs of the morphine group, as we have learned, exert a 
preponderating] y depressing influence on the central nervous system 
of vertebrates and produce in invertebrates quite different effects 
and in vegetable organisms no effects at all. 

The next group which we have to consider is a large and quite 
different one, consisting of substances whose actions, while preponder- 
a tin tily depressing ones, are not confined to the central nervous system 
of vertebrates, but are exerted on all types of animal organisms and 



HYDROCARBON HYPNOTICS 43 

affect not only nervous tissues but all living protoplasm. This is 
the group of alcohol [spoken of also by various authors as the 

ALCOHOL-CHLOROFORM GROUP, the GROUP OF HYDROCARBON NARCOTICS, 

etc. — Tr.] This somewhat arbitrarily named group includes, as a 
matter of fact, all indifferent organic carbon compounds which are 
soluble in fats, with the exception of such hydrocarbons as are not 
volatile and are entirely insoluble in water, and are consequently in- 
capable of absorption by the organism. Among its members may be 
found simple and substituted hydrocarbons, alcohols, aldehydes, 
ketones, ethers, esters, acid amides, substituted ureas, and other types 
too numerous to mention. 

Of this practically unlimited number of substances only a rela- 
tively few are actually employed as medicines, which are variously 
known as hypnotics or sedatives and as anaesthetics, according as their 
action is more or less pronounced or lasting or evanescent. Ethyl 
alcohol occupies an intermediate position between these two classes, 
connecting them and belonging, as it were, to both. Consequently its 
properties and actions should be discussed first of all. 

Alcohol. — Ethyl alcohol, C 2 H 5 OH, is formed from sugar by yeast 
fermentation. When during the fermentation about 18 per cent, 
of alcohol has been formed, the fermentation ceases, but may be started 
up again by dilution with water. It is thus evident that even yeast 
cells are paralyzed by a certain concentration of alcohol in the sur- 
rounding fluid, and this power of alcohol to depress or paralyze 
functional activities is found to hold good for all forms of living- 
organisms. 

Symptoms of Stimulation after Alcohol. — Often, but by no 
means always, the depressing effect of a drug is preceded by a stimu- 
lating one, and it is desirable to determine whether or not this is also 
the case with alcohol. As a matter of fact, in man the first, and, 
at the start, the only noticeable effects produced by it, are exaggerated 
talkativeness and motor restlessness, quickened breathing and pulse, 
and flushing of the face, all apparently signs of stimulation, which 
are followed, only when larger amounts are consumed, by a general 
depression and a feeling of fatigue, and by slowed respiration and 
circulation, and diminution of all reflexes. 

It has been demonstrated that the primary action, responsible for 
Ihis apparent stimulation, occurs in the cerebral hemispheres, for the 
less the cerebral development of* the animal the slighter are the appear- 
ances of stimulation, and, as Baratynsky showed in frogs and pigeons, 
which, though decerebrated, were kept alive for months, these do not 
occur at all if the cerebrum has been removed. 

The nature of this excitement or stimulation has been the subject 
of much discussion. Before starling in on such discussion it is desir- 
able t li.it the SIGNIFICANCE OF stimulation be thoroughly understood. 

Every expression of life, whether conscious or unconscious, is a 



44 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

reaction, — i.e., a response to a stimulus. It is impossible for any 
change, movement, or other functional activity in a living organism 
to occur spontaneously, — that is, without a sufficient cause. If any 
substance by its action in the body causes a reaction, there are three 
ways in which it can do so. It may do this: (1) by acting itself as 
a direct stimulus (as does NaCl when applied to nerves) ; (2) by 
making it possible for other constantly occurring but ordinarily sub- 
liminal stimuli to become efficient; or (3) by bringing it to pass 
that the discharge of energy which results from a given effective stimu- 
lus produces results which are more wide reaching or violent than 
usual. The first we call direct stimulation, the others exaltation" 
of the excitability. The first may be compared to the closing of the 
quicksilver contact in an electric circuit, the second to the rendering 
the points of contact more delicate, and the third to the removal from 
the circuit of resistance coils or the interpolation of better conductors. 
It is evident that in the last two cases, which, by the way, usually 
cannot be differentiated from each other, we are dealing with an 
alteration in the functional condition of the physiological mechanism 
in question, which causes either an acceleration of the reaction or a 
removal of inhibition. 

We must look on all the functional activities of cells as resulting 
from chemical processes, either katabolic (disintegrative) or anabolic 
(constructive or synthetic) in nature, the former accompanied by a 
discharge of energy, the latter leading to its reaccumulation. These 
reactions in the cells may be accelerated by catalyzing agents or 
retarded by inhibiting ones, in a fashion quite analogous to that in 
which chemical reactions may be modified by appropriate agents. 
Increased discharge of energy — that is to say, increased functional 
activity, or stimulation — results alike from the removal of in- 
hibiting FORCES OR THE INTRODUCTION OF ACCELERATING ONES. 

The removal of inhibition is perhaps the more common phenomenon, 
for in the majority or perhaps in all organs the functions are in a state of 
halance or rivalry, each function normally being limited or inhibited by an 
antagonistic one. The elimination, by depression or paralysis, of any function 
thus results in the initiation or augmentation of the activity of the correspond- 
ing antagonistic one. This connection, moreover, obtains not only between 
antagonistic functions but also between those which produce similar effects 
and which, as it were, compete with each other. For example, the elimination 
of the cardiac vagus of one side causes an augmentation in the excitability of 
that of the other side, this indicating apparently that there is a certain com- 
petition between the influences exerted on the peripheral cardio-inhibitory organs 
by the vagi of the two sides (v. Tschermak) . In a similar fashion centrifugal 
stimuli compete in the terminal nervous organs with chemical stimuli which 
act in the periphery. Thus the excitability by chemical agen£s of the peripheral 
dilator mechanism of the cat's iris is augmented by section of the cervical 
sympathetic, which is the ordinary path for impulses coming from the centre 
to this organ. 

With Goltz and J. Loeb we attribute to the cerebrum the functions 
of inhibition and exclusion, which alone render possible the concen- 



ALCOHOL 45 

tration of the attention and will on the acts of perception or motion 
needed at the time, without regard to all other centripetal or cen- 
trifugal processes in the central nervous system. It seems plausible, 
then, to assume that the early effects of alcohol are limited to a weaken- 
ing of this inhibiting function of the cerebrum, while the lower por- 
tions of the central nervous system are not directly influenced by it. 
As a result of this removal of inhibition, we see the evidence of 
their exaggerated activity in the tipsy individual's unrestrained be- 
havior, his loquacity, his tendency to laugh or weep without cause or 
to burst into a tempest of rage. As in certain cases of bilateral disease 
of the cortex analogous symptoms occur, it would appear that the 
above assumption satisfactorily explains such symptoms. In the same 
way the faulty control of equilibrium and the loss of muscle sense in 
intoxication indicate a direct depression of the cerebellar functions. 
However, it cannot be absolutely denied that a direct stimulating action 
is exerted by alcohol on the basal ganglia and on certain centres in the 
medulla, and that this plays an important part here, especially in 
connection with the symptoms of stimulation of the motor portions of 
the brain. 

Motor Excitement. — It is well known that symptoms of motor 
excitement result from the administration of alcohol, and it is to 
these effects that it owes its reputation as a reviving and strengthen- 
ing agent, of which use is gladly made in cases of fatigue or bodily 
weakness or to aid in the performance of heavy tasks. It is only in 
the last decades that an exact and complete proof has been brought 
that alcohol actually does cause such motor excitation. W. Lombard, 
using Mosso 's ergograph, was able to show that, when small quantities 
of alcohol were taken, the power of performing voluntary muscular 
work was not directly increased, but the development of the feeling 
of fatigue was postponed, so that more voluntary work was per- 
formed by the muscles. This, however, is not due to an increase in the 
capacity of the muscles, for, when involuntary muscular contractions 
were produced by peripheral electric stimulation, alcohol lessened the 
capacity for muscular work. From these residts it is clear that the 
increase in capacity for work is central in its causation and is purely 
the result of retardation of the development of the sensation of fatigue. 
Frey, Krapelin* and his collaborators, and Joteyko have confirmed 
these observations, but Rivers was not able to do so. Kr'dpelin's* 
physiological discussion and Joteyko's very plausible explanation of 
the ergographic records, which is based on a mathematical analysis, 
both indicate that a facilitation of the cerebral motor processes is 
involve! in these results (see Pharmacology of the Muscles, p. 422). 



As fchie facilitation of the motor processes can be broupht about as often 
ae wished by repeating tin- administration of small amounts of alcohol, Kr&peVm 
assumes it to !><• tlie result, of a direct hut very temporary exaltation in the 
excitability of the motor tracts and not the result of a temporary weakening 



46 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

of inhibition. However, this argument is not convincing, for a temporary de- 
pression of the inhibitory centres by alcohol may be assumed just as readily as 
a temporary excitation of the motor ones, and therefore it could just as well 
be repeatedly induced. 

Still less valid is the opposing view that the direct action of alcohol 
is always a depressing one, and that the " stimulation " produced by it is 
only an" apparent one, due only and always to depression of inhibition or dis- 
turbance of the normal balance in the cerebrum, etc. As a matter of fact, it has 
been shown that alcohol does produce a direct augmentation of the excitability 
in isolated frog's nerves (Mommsen, Efron, Breyer), in nerve-muscle prepara- 
tions (Scheffcr and others), in ciliated epithelium {Engelmann, 18G8; Breyer, 
1903), and also in plant cells, in which alcohol accelerates the flow of plasma 
(E. Josing). All of this being so, it is hard to see why it should not cause 
similar stimulation of central nervous organs also. Apparently it is largely a 
question of terminology, for the utilization of current in an electric circuit may 
be increased just as well by lessening the resistance, by shortening the circuit, 
or by cutting out a portion of it, as by improving a portion of the conducting 
path, and, whether the conduction is improved and the resistance thus lessened 
or whether the conduction for a competing or antagonistic current be lessened, 
the result is the same, for it is always a question simply of supplying greater 
current energy through the excited segment and not of the production of energy. 

The "stimulation" from a single dose of alcohol is never of 
long duration, lasting only for 30 to 60 minutes, and with larger 
amounts it is quickly followed by depression. For abstemious adults 
the limits for such ' ' stimulating ' ' doses may be placed at about 30^0 
grammes of alcohol, corresponding to 250-500 c.c. of wine or a litre 
of beer. For those accustomed to the use of alcohol the dose must 
naturally be somewhat larger. 

In addition to facilitating the performance of motor acts, alcohol 
also, especially in sickness or exhaustion, when such may be accom- 
plished only by considerable effort of the will, produces a feeling of 
increased strength and of general ivell-being. Other physiological 
processes, such as those of nutrition and metabolism, may be indirectly 
influenced in a favorable sense by the improved nervous condition. 
In this way one phase of the analeptic, stimulating action of alcohol 
is sufficiently explained. Moreover, it is a well-known fact that 
when alcohol is taken frequently, there quickly develops a habituation 
to the effects produced on the nervous system, so that the stimulation 
felt at the start is no longer experienced unless the amounts taken are 
increased. Consequently it is clearly evident that the habitual daily 
use of alcohol is not only incapable of facilitating or improving the 
performance of physical work, but that, on the contrary (on account 
of its other harmful actions), it impairs it. The experience obtained 
in different wars and in sports is in complete accordance with this 
view. 

Respiration. — The other side of the stimulating action of alcohol, 
in so far as the central nervous system is concerned, deals with its 
effects on the respiration. This is strengthened so that the respiratoiy 
volume — i.e., the amount of air respired in a unit of time — is in- 
creased. This is due not only to reflex stimulation through the 
senses of taste and smell and from the bronchial and stomach nerves, 



ALCOHOL 4? 

or to increased muscular activity, but probably also to a direct 
stimulation of the respiratory centre (Wilmanns and others). This 
strengthening of the respiration occurs even in sleep and after doses 
which cause sleep, and consequently this action may be of value clini- 
cally in cases of poisoning or shock. However, the more volatile 
members of the alcohol group (ether, acetic ether, etc.) are in this 
respect more efficient and useful. It goes without saying that such an 
artificial strengthening of the respiration can be of no value to healthy 
hard-working men. 

Effects on the Powers of Perception and Association. — As 
far as has been shown up to the present, most of the functions of the 
central nervous system are depressed by alcohol. This is especially 
so for the faculties of perception and association. This is evident 
from the general experience that judgment is never improved by 
alcoholic indulgence, but is always impaired, and the exactly conducted 
psychological studies of Krapelin V and his collaborators led them 
to the same conclusions. 

Effects on the Mood. — The sensation of physical and psychical 
well-being is determined by the intensity of the feelings of discomfort 
and by the intensity of the inhibitions, under whose constantly varying 
influence we exist, for positive feelings of pleasure can never be con- 
sciously experienced except for the time being and, according to the 
law of Weber and Fechner, must consequently disappear if the 
stimuli remain the same. The feeling of health in a similar fashion 
means nothing else than the failure to be conscious of any pathological 
disturbance. From this it necessarily follows that any general blunt- 
ing of the perception and conception of life must lead to an euphoria, 
and if, in every-day life, "wine makes glad the heart of man," it is 
self-evident that this must be even more true for an invalid suffering 
in body and soul. As a matter of experience, almost all the functions 
of the body, the appetite, and, depending on it, the digestion, the 
metabolism, the circulation, the respiration, and the ability to sleep, 
are very markedly affected by the general subjective condition, — i.e., 
by the intensity of the subjective euphoria. Therefore, it is evident 
that, in proper cases, alcohol may be a very valuable medicament for 
the preservation and augmentation of the strength of the invalid. 

However, it is important to emphasize the fact that in many 
nervous patients any amounts of alcohol, even very moderate ones, 
can produce harmful effects. This is the case, among others, with 
epileptics, whose condition of depression in many particulars resem- 
bles that caused by alcoholic intoxication, and may be most strikingly 
aggravated as a result of the consumption of alcohol (Krapelin"). 
Moreover, it should not be forgotten that grave harm may result from 
advising long-continued or regular use of alcohol for the purpose of 
strengthening a patient, or of stimulating his appetite and calming 
his nerves, and that, under all circumstances, this is particularly 



48 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

dangerous advice to give to neurasthenic patients in whom the will 
power is weak. 

Large doses of alcohol cause blunting and complete paralysis of 
the functional activity of the cerebrum. The consciousness and the 
cerebral reflexes are abolished. The centres for the regulation of heat 
and the spinal centres are paralyzed, and finally, when fatal doses 
have been given, the excitability of the respiratory centre in the-meclulla 
is completely abolished. Therapeutically this narcotic action of alco- 
hol may be utilized in the symptomatic treatment of conditions of 
excessive excitability of the reflex centres, as, for example, in strych- 
nine poisoning. This is especially the case if other, perhaps more 
appropriate, remedies are not at hand. It is also of some interest 
that some savage races are accustomed to intoxicate to a state of 
complete insensibility (Felkin), with palm wine or other alcoholic 
beverages, any one about to*be operated upon, and under certain con- 
ditions this could be done, in case of need, even in civilized lands. 
However, it is impossible to estimate beforehand, with any certainty, 
the duration of the primary stage of excitement or that of the complete 
narcosis with abolition of the reflexes. In addition to this decided 
disadvantage, the use of alcohol as an anaesthetic possesses also the 
disadvantage that it is followed by long-continued extremely dis- 
agreeable after effects.* 

Circulation. — Inasmuch as alcohol, as has already been men- 
tioned, exerts its action not only on the nervous tissues but also 
on all living protoplasm, in man its effects are not limited to those 
on the functions of the central nervous system, but are exerted with 
greater or lesser intensity on the functions of all organs. At this 
time these will be discussed only in so far as appears necessary to 
secure a proper understanding of its greatest action. A part of this 
is a strengthening of the cardiac action and an acceleration of the 
pulse, which in health occurs to but a slight degree or not at all, but 
which in disease is often manifested in a very useful and striking 
fashion (see pp. 258, 316). 

Alcohol also depresses the tone of the vasomotor centres and thus 
dilates the vessels, particularly the cutaneous ones. The feeling of 
warmth, which is obtained by drinking alcohol when cold, depends on 
this dilatation of these- vessels, for our sensations of warmth depend 
entirely on the condition of the terminal organs of the cutaneous tem- 
perature nerves. That is to say, the better the circulation in the skin 
the warmer we feel. Consequently, even small doses of alcohol, as a 
result of this dilation of the cutaneous vessels, produce a deceptive 

* According to Finlcclnburg, alcohol causes a rather lasting stimulation of 
the secretion of the liquor cerebri and consequently an increase in the sub- 
arachnoid pressure. It is not impossible that the post-alcoholic headache is due 
to this increase in intracranial pressure [for spinal puncture can often bring 
prompt and striking relief. — Tb.]. 



ALCOHOL 49 

feeling of warmth, in spite of the fact that larger amounts of heat are 
lost by the body as a result of bringing heat from the interior of the 
body to the surface where it is given off. 

After non-narcotic doses this greater loss of heat is not compen- 
sated for by an increase in the production of heat, for after large 
doses the heat-regulating nerves, like the other cerebral centres, are 
depressed and the regulation by chemical means becomes inadequate, 
and consequently the temperature of the body is markedly lowered. This 
is an explanation of the danger of an intoxicated individual 's freezing 
to death in winter. As will be more fully discussed in the section on 
antipyresis, the disturbance of the heat-regulating mechanism is espe- 
cially pronounced in fever, and in former times alcohol was used as 
an antipyretic. As a matter of fact, its thermic action is in principle 
not at all different from that of the true antipyretics, but it is devel- 
oped only after doses which produce marked effects on other functions. 
Consequently, alcohol should not be used as a specific antipyretic, 
any more than arsenic should be used as an emetic although its emetic 
action is entirely similar to that of antimony. 

Antiseptic Action. — As a result of certain clinical observations, 
the claim has been made that alcohol can exert antiseptic and bacteri- 
cidal actions after it has been absorbed into the blood ; but this assump- 
tion has no valid foundation. As far as it is possible to draw any 
conclusions from the experimental observations of Laitinen, it, on the 
contrary, diminishes the resistance to bacterial infection. That, how- 
ever, patients with septic fever can support very unusually large 
amounts of alcohol without becoming intoxicated is a noteworthy fact, 
which has been observed, and which may be explained in the same 
way as the unusually high resistance to morphine exhibited by dogs 
poisoned by atropine (Binz). It is also possible that in fever alcohol 
is combusted more rapidly than in health, but thus far this has not 
been investigated. 

Externally, however, on account of its solubility in fat and water, 
and on account of its power of hardening the tissues, alcohol may be 
advantageously used as a disinfectant (Ahlfeld). On account of 
these same properties, when alcohol is rubbed on the skin it penetrates 
the epithelium and causes a local irritation of sensory and vasodilator 
nerve-endings and may be used as a counterirritant. 

The Fate of Alcohol in the Body. — Alcohol, with the exception 
of slight traces (2-5 per cent.) which leave the body through the 
lungs, is completely burned in the bodies of warm-blooded animals, 
self-evidently with a corresponding production of heat. According 
to I'ritujsln in,, animals accustomed to alcohol combust it more rapidly 
,1|;| " the unhabituated controls, its combustion taking place in about 
two-thirds of the time which is necessary for the combustion of similar 
doses when administered to the controls. 

It has been established by numerous investigators (Atwater, R. 0. 

4 



50 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Neumann, Rosemann, and others) that calorically equivalent 

AMOUNTS OP THE CARBOHYDRATES AND FATS OP THE BODY MAY BE PRO- 
TECTED FROM COMBUSTION BY THE METABOLIC COMBUSTION OF ALCOHOL. 

Under certain circumstances it appears to be able to act as a physio- 
logical substitute for the carbohydrates, aside from the utilization of 
its caloric energy value, a fact which appears not without importance. 
In diabetic acidosis the administration of alcohol, like that of carbo- 
hydrates, decreases the formation of acetone (Neubauer) [and also 
that of the pathologically more important oxybutyric acid. — Tr.]. 
Alcohol ma}' therefore, in so far as its toxic side actions may be disre- 
garded, be considered as a surrogate for food, and may occasionally 
be useful as such in the treatment of disease. 

BIBLIOGRAPHY 

Ahlfeld: Volkmann's Samml. klin. Vortr., Nos. 310, 311, 1901. 

Baratynskv : Arch, des science biol. St. Petersbourg, 1894, vol. 3, p. 167. 

Binz: Zbl. f. klin. Med.. 1893, vol. 14. 

Breyer: Pfliiger's Arch., 1903, vol. 99, p. 481. 

Efron: Pfliiger's Arch., 1885, vol. 36, p. 467. 

Felkin: Lage und Stellung der Frau bei der Geburt., Dissert. Marburg, 1885. 

Finkelnburg: D. Arch. f. klin. Med., 1904, vol. 80. 

Frey: Mitt, aus Klin. d. Schweiz., Series 4, 1896, vol. 1. 

Fiihner: Miinchn. med. Woch., 1911, No. 4. 

Josing, E.: Jahrb. f. w. Botanik., 1901, vol. 36. 

Joteyko: Trav. du labor, de l'inst. Solvay, Bruxelles, 1904, No. 6, p. 4. 

1 KrJipelin: Ueber d. Beeinflussung einf psychischer Vorgiinge durch einige 

Arzneimittel, Jena, 1892. 
2 Kriipelin: Miinchn. med. Woch., 1899, No. 42. 
3 Hoch u. Krapelin, Psychol. Arbeiten, 1895. 

Laitinen: Ztschr. f. Hygiene u. Infektionskrankh., 1900, vol. 34, No. 2. 
Lombard, Warren: Journ. of Physiol., 1892, 13. 
Mommsen: Virchow's Arch., 1881, vol. 83, p. 243. 
Neubauer: Miinchner med. Woch., 1906, No. 17. 
Neumann, R. O.: Arch. f. Hygiene, 1899, vol. 36; Miinchn. med. Woch., 1901, 

No. 28. 
Pringsheim: Bioehemisehe Zeitschr., 1908, vol. 12. 

Rivers: The Infl. of Alcohol and other Drugs on Fatigue. London, 1908. 
Scheffer: Arch. f. exp. Path. u. Pharm., 1900, vol. 44, p. 24. 
v. Tschermak: Monatshefte f. Psvch. u. Nerol., 1909, vol. 26. 
Wilmanns: Pfliiger's Arch., 1897,' vol. 66, p. 167. 

GENERAL ANESTHETICS 

While studying the action of alcohol on the central nervous 
system, we have at the same time been learning the typical effects of 
a very large number of other substances, of which the greater number 
belong to the aliphatic series. These are those hydrocarbons, alcohols, 
ethers, esters, etc., of an indifferent nature, possessing neither acid nor 
alkaline properties, nor those of the salts, and which are characterized 
less by their chemical than by their physical affinity for certain con- 
stituents of the protoplasm. Some other substances which do not be- 
long to the aliphatic series — as, for example, nitrous oxide or carbon 
dioxide — also are to be considered as belonging pharmacologically 
to this great alcohol group. Naturally, though, of all this large army 



GENERAL ANAESTHETICS 51 

of substances, only a few are practically useful in medicine, — namely, 
those whose narcotic action is relatively a pure one and at the same 
time sufficiently powerful. 

However different, on superficial observation, may be the appear- 
ance of an ether narcosis, which is well developed but which lasts 
but a short time, from that of the merely calming but rather persistent 
effect of a small dose of sulphonal, in their nature the actions of these 
drugs are essentially similar, but in the two cases we utilize entirely 
different degrees or phases of an action which in principle is identical. 
In each case these substances, whether classed as hypnotics or anaes- 
thetics, when given in large doses, by their depressing action abolish, 
for the time being, the functions of the brain and also those of the 
spinal cord, while the respiratory centre is still able to perform its 
functions satisfactorily and the circulation remains comparatively 
little affected. In anaesthesia produced by ether or chloroform, the 
fact that they are administered through the lungs makes it possible 
very accurately to induce that degree of their pharmacological action 
which is just this side of the danger line, and to maintain this con- 
dition only as long as appears necessary for the painless accomplish- 
ment of the operation. In contradistinction to this, when hypnotics 
are used, it is only the early stage of the general "alcohol" action 
which is utilized, during which stage the excitability of certain func- 
tional tracts in the cerebral cortex is depressed only to a slight degree. 

Historical. — Medicine owes the discovery of general anaesthesia 
to experiments which were made to determine the effects of chemically 
pure gases on human beings. When, toward the end of the eighteenth 
century, the science of chemistry was occupying itself with various 
gaseous substances, the effects of these gases in human beings was 
frequently studied, and in fact the attempt was made to utilize these 
effects in the treatment of disease. The intoxicating effects of nitrous 
oxide were discovered early in the nineteenth century by the English 
physicist, Ilumphry Davy, who recognized that "among other proper- 
ties nitrous oxide appears to possess the power of relieving pain," 
and he suggested that it could be advantageously used for surgical 
operations. However, the fact that the condition of intoxication 
observed was merely a forerunner of a true narcosis was not recognized 
by Davy or his contemporaries, perhaps because of the difficulty of 
handling the gas. 

Consequently experiments with the inhalation of nitrous oxide went 
out of fashion, and were only now and then conducted for the pur- 
pose of demonstration, in spite of the fact that at the start they had 
been described with great enthusiasm and had been frequently re- 
peated. It was due to such a demonstration in Hartford, Conn., that 
thr dentist, IF. Wells, in 1844, forty years after Davy's discovery, 
rediscovered nitrous oxide anaesthesia. 



52 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

He noticed that one of the persons to whom this gas had been administered, 
after inhaling it staggered about in a somewhat intoxicated condition, and hap- 
pening, while so doing, to receive a by no means slight injury, exhibited no signs 
of suffering. Wells, however, did not succeed in introducing nitrous oxide 
anaesthesia into practice, his endeavors to do so remaining fruitless on account 
of the difficulty with which the gas could be handled and because it was not 
suitable for major operations. It was only at a much later date that an improved 
technic permitted this method of anaesthesia to be widely adopted. 

However, the idea of inducing anaesthesia by causing a gas to be inhaled 
was pursued further, with happier results, by an eye-witness of Wells's earlier 
experiment, Morton, a Boston dentist, who in cooperation with the chemist, 
Jackson, sought for some gas more suitable for this purpose. Jackson suggested 
that experiments be made with ether, whose intoxicating effects on human beings 
were already known, and which possibly some surgeons may have employed even 
before this time. 

In 1846 in the Massachusetts General Hospital of Boston, Morton 
and the surgeon, Warren, performed the first major operation under 
ether. This discovery was communicated to the Academy in Paris 
in 18-47, and in the same year Flourens also made the communication 
to the Academy, that, in experiments on animals, chloroform pro- 
duced the same effect as ether, except that it anesthetized them more 
deeply and more rapidly. In 1847 Simpson of Edinburgh made use 
of chloroform anesthesia in human beings for the first time. 

This most important step of progress was entirely due to the dis- 
covery of volatile narcotic substances, for no other path of absorption 
is so adapted for the rapid attainment, without danger to life, of that 
degree of pharmacological action adequate to produce anesthesia, and 
at the same time so adapted to facilitate its rapid diminution at any 
chosen moment, as is the path of absorption through the lungs. All 
the narcotics administered by the stomach which had formerly been 
used for the induction of surgical anesthesia (mandrake, opium, and 
alcohol) suffer from the disadvantage that their actions develop far 
more slowly and possess the even greater drawback that, when once 
the dose had been administered, one is entirely unable to prevent a 
further rise in the concentration of the drug in the blood if this be 
undesirable. 

Volatility op Prime Importance for the Practical Use of 
General Anaesthetics. — For the rapid attainment of a complete 
anesthesia, the most rapid path of absorption of the narcotic must be 
available, and it is equally important that its excretion shall also take 
place by an equally rapid route, in order that its concentration in the 
blood may at any time be altered as occasion arises. When ether and 
chloroform are used as anesthetics, the interruption of its inhalation 
suffices immediately to transform the portal of entry for the narcotic 
into a most efficient organ of excretion. 

The surprising rapidity with which volatile substances are absorbed 
from the lungs into the blood and pass out of the blood into the 
expired air is readily explained by the nature of the mechanism of 
the absorption of oxygen and excretion of C0 2 in the lungs. The 



ANAESTHESIA 53 

enormous surface of the pulmonary capillaries, from which the alveolar 
air is separated by a membrane composed of only one layer of cells, 
supplies all the conditions for the most rapid interchange of gases 
and vapors. However, this path is not available for all gases, for 
such vapors as chlorine or sulphurous acid, by their irritating effects, 
produce a spasm of the glottis and other reflexes in the upper air- 
passages so that the lungs are protected from them. Consequently, 
only such gases or vapors may be used as anaesthetics as are relatively 
non-irritating and consequently do not cause such defensive reactions 
to too great an extent, although they are clearly produced with a 
certain degree of intensity by chloroform and especially by ether. 

GENERAL ANAESTHESIA 

Among the narcotic gases and vapors which may be inhaled and 
which meet the conditions necessary for their absorption through the 
lungs, ether and chloroform, and, especially for short operations, ethyl 
bromide, ethyl chloride, and nitrous oxide, are practically the only 
ones which need be considered. When properly administered, these 
all produce a condition of complete insensibility and unconsciousness, 
— a general anaesthesia. The term, " general anaesthesia," is used for 
this condition in contradistinction to that of local anaesthesia, in 
which the abolition of sensibility is obtained by the paralysis of the 
sensory nerve-endings at the seat of the operation. 

In the induction of anaesthesia, before complete anaesthesia is in- 
duced the perception of impressions from without is abolished, so that, 
even at the time when consciousness is still preserved and is only 
somewhat clouded, painful procedures are hardly perceived at all, a 
condition of analgesia having been attained. When nitrous oxide 
anaesthesia is employed, as a rule, one does not go beyond this stage. 
In deep ether or chloroform anaesthesia, on the other hand, the con- 
sciousness is completely abolished and voluntary motions cease, just 
as in profound sleep. Under these conditions the lower portions of the 
cerebrum, the basal ganglia, etc., are put out of function, as it were, 
and later the spinal cord is similarly affected, so that the tone of the 
voluntary muscles is abolished and the operation is not disturbed by 
any reflex movements. Only respiration, circulation, the interchange 
of gases in the lungs, and the metabolism of the tissues remain approxi- 
mately normal during the anaesthesia. The art of anaesthetization 
consists largely in preventing the extension of such effects to the 
respiratory and circulatory centres. 

Ether (diethyl ether, CUI-OCJIJ, also called sulphuric ether, 
on account of its manufacture by heating alcohol with sulphuric acid, 
is a clear, colorless fluid, with a peculiar smell and burning taste, 
Which boils at 35° C. [U.S.P. 36-37° C.]. This low boiling point is 
of l: rr.it importance, for it is the expression of its great volatility, which 
is of the greatest importance for its administration as an anaesthetic. 



54 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

At ordinary temperatures the evaporation of ether occurs rapidly and 
is accompanied by well-marked loss of heat, so that it may produce a 
cooling to temperatures far below 0° C. 

Ether is miscible with oils and alcohols in any proportions, and is 
soluble in water in the proportion of one part in 12 at 17° C, while 
one part of water is soluble in 35 parts of ether. Contamination of 
ether by water or alcohol changes its boiling point and specific gravity 
[0.725-0.728 U.S. P.] and can consequently be readily recognized. 
Among other tests for purity prescribed by the pharmacopoeia are, 
that it should not color litmus paper nor be colored within an hour 
with a solution of potassium hydrate. Ether which is to be used for 
anesthesia should be shielded from light and should be kept in tightly 
stoppered containers, as it is itself very inflammable and, as a mixture 
of ether and air explodes with great violence, ether narcosis should 
not be conducted in the presence of unprotected flames. 

Local Irritant Action. — Ether vapor, being very volatile, has a 
high vapor tension, even when it is dissolved in the body fluids, and 
consequently it penetrates the tissues with extreme ease, irritating, 
at the point of application, susceptible tissue elements, particularly 
the nerve-fibres and the vessel walls. When ether thus penetrates the tis- 
sues, the sensory nerve-endings are first intensely irritated for a short 
time, then their sensibility is depressed. These effects in the nerve- 
endings, combined with the cold produced by its evaporation, account 
for the local anesthesia of the skin which may be produced by this 
drug, in which connection this action will be further discussed (p. 118). 

The local irritation of the sensory nerve-endings also explains cer- 
tain indirect effects on the central nervous system, for a certain por- 
tion of the effects produced by ether on the respiratory and circulatory 
centres is certainly due to reflexes caused by such sensory irritation. 

The action of ether after absorption into the blood is almost exclu- 
sively exerted on the central nervous system, for, even when the 
paralysis of most of the functions of the central nervous system is 
well developed, the circulation is but little affected, ether behaving 
in this respect like alcohol. In general terms, the action of ether may 
be characterized as an "alcohol action," which is concentrated in a 
short period of time and which is very pronounced. The chief differ- 
ence is that, on account of the rapid absorption of ether, especially 
when it is inhaled, the earlier stages of the effects on the cerebrum 
are less prominent than is ordinarily the case in alcoholic intoxication. 
However, in the first stage of the action of ether, we find the same 
peculiar mixture of depression of some functions of the cerebrum 
and of motor excitation which has been described in the analysis of 
the action of alcohol. In the second stage of the action of ether, the 
anesthesia is completely developed, just as is the case in very pro- 
found alcoholic intoxication, with depression of all the cerebral func- 
tions and also of the spinal reflex mechanisms, the centres in the 






ETHER, CHLOROFORM 55 

medulla being the last to be affected and the heart beating relatively- 
well even when death results from cessation of the respiration. 

Excretion. — Ether is excreted in the expired air, by far the largest 
portion leaving the body very rapidly. 

As the effects of ether on the central nervous system in general 
agree with those of chloroform, these two drugs can well be considered 
and discussed together. 

Chloroform, trichlormethane, CHC1 3 , is a clear, colorless fluid, 
boiling at 62° C, the vapor having a sweetish odor and taste. It is 
very slightly soluble in water (about 1 : 200), but miscible with alcohol, 
ether, and the fatty oils in any proportion. Iu contradistinction to 
that of ether, chloroform vapor is neither inflammable nor explosive. 
However, the anesthetization with chloroform in the presence of gas- 
lights is attended with certain disadvantages, as, in the combustion 
of its vapor, the gas, phosgen, CC1 2 0, and hydrochloric acid are formed, 
both of which are very irritant to the mucous membranes (Gerlinger) . 

Properties. — As chloroform decomposes readily under the influence of light 
and air, it should be kept in opaque and completely filled containers. As the 
addition of a small amount of alcohol renders it more stable, the pharmaco- 
poeia permits it to contain 0.6-1 per cent, of alcohol. 

Liebig and Houbeyran prepared chloroform for the first time at about 
the same time, — the former by allowing KOH to act upon chloral, and the latter 
by distilling alcohol with chlorinated lime; the latter method of preparation 
being the one which is more generally used. If impure alcohol is used in its 
manufacture, an impure product is obtained which must be purified. A com- 
pletely pure chloroform may be obtained from chloral by decomposing it with 
soda, while other pure forms may be obtained by distilling acetone with chlo- 
rinated lime or by crystallizing chloroform by cooling to — 70 to — 80° C, 
or from its crystalline compound with salicylic acid anhydride. However, these 
absolutely pure chloroforms possess no advantages for medicinal purposes over 
the chloroform of the pharmacopoeia, which has a specific gravity of 1.490. 

The Pharmacopoeial tests for the detection of impurities are reliable and 
give a guaranty of its purity quite sufficient for its employment by physicians. 
[If some chloroform be allowed to evaporate in a watch-glass, the last drop should 
have an irritant effect when inhaled. Distilled water shaken up with chloroform 
should give no reaction with potassium iodide and starch, nor with silver nitrate, 
DOT Bhould such water redden litmus paper. When left in contact with concen- 
trated sulphuric acid, chloroform should not be darkened in color in less than 
one hour. — Tr.] 

Local Irritant Action. — In equal concentration chloroform is far 
more irritant to the tissues than is ether. When applied to the exter- 
nal skin, it causes first a feeling of coolness due to evaporation, then 
burning and reddening. If its evaporation is prevented, it may cause 
active inflammation and the formation of blisters. Dissolved in oil it 
produces a less intense but more lasting irritation of the skin. Its 
local irritant effects are even more pronounced on the mucous mem- 
branes, so that, when poisoning has resulted from swallowing chloro- 
form, serious lesions of the stomach and bloody vomiting and diarrhoea 
result. 

Excretion. — Much the larger portion of the chloroform is excreted 
through the lungs and with great rapidity, but a small portion is 



56 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

decomposed in the body, and as a result the chlorides in the urine 
are increased (Zeller). 

The narcotic action of chloroform, as also that of ether, is a very 
gt neral one. Wherever in the organic world sensory and motor phe- 
nomena are to be found, these expressions of life are abolished if these 
anaesthetics are applied in sufficient concentration. The alterations 
in cell functions caused by them may be best observed if motor 
phenomena occur as a visible expression of cell life. In plants they 
abolish the movement of the protoplasm. The experiments on the 
sensitive plant, Mimosa pudica, the irritability of which is, for the 
time being, abolished by the action of anaesthetics, is a striking demon- 
stration of such action (D ut rochet, Leclerc, P. Bert) (for further 
literature on the action of narcotics on plants see 0. Bichter) . Their 
influence on motor phenomena in animal cells may be very simply 
demonstrated on ciliated epithelium, the ciliary movements of the 
epithelium in the mucous membrane of the posterior portion of the 
frog's throat being no longer able to move a small particle placed 
on its surface if it be exposed to an anaesthetic gas. 

With a more pronounced degree of toxic action, death ensues in 
the cells of all tissues, the red blood-cells are destroyed by stronger 
concentrations, and rigor of the muscles ensues (Kussmaul) and the 
peripheral nerves are rendered unexcitable (/. Bernstein) . However, 
all such effects, which may be produced by anaesthetics on the blood, 
the muscles, and the peripheral nerves outside of the body, are of no 
significance in connection with the use of the anaesthetics in medicine, 
for the central nervous system and also the heart are so much more 
susceptible that death occurs as a result of paralysis of the respira- 
tion and the heart long before these cells are affected. [Some destruc- 
tion of the red cells does, however, occur during ordinary anaesthesia, 
particularly if this be prolonged or is very deep. — Tr.]. It is owing 
to this much greater susceptibility of the nervous system tJiat ances- 
thetics, which are fundamentally toxic to all living cells, may be. 
employed to influence solely the functions of perception and action. 
They may be used as anaesthetics primarily because they depress first 
the cerebrum and then the spinal reflex centres, while the respiratory 
centre resists their paralytic action longer than all other portions of 
the central nervous system. 

Clinical Picture of General Anesthesia. — At the commence- 
ment of the anaesthesia a condition resembling intoxication develops, 
during which the consciousness is clouded and is occupied by confused 
ideas. At this time there is more or less well-developed motor rest- 
lessness, and consequently this is often spoken of as the stage of excite- 
ment. Loud and foolish talking, laughing, etc., and active movements 
may occur, thjf face being reddened and the pupils dilated. While 
these symptoms of excitement are in many cases, particularly in 
women and children, but little developed and pass off rapidly, in 



GENERAL ANESTHESIA 57 

men, and especially in potators, they may be so marked as to resemble 
delirium of maniacal attacks. The more rapidly the concentration of 
the anaesthetic in the blood increases, the more rapidly does this stage 
pass over into that of complete unconsciousness. "When this develops, 
the eyes assume the same position as in normal sleep, being turned 
inward and upward and the pupils being somewhat contracted. The 
sensibility is already abolished, although the reflexes still exist at this 
stage, and, in fact, even earlier, at a time when the sense of touch is 
but slightly impaired and when the patient may still be awakened by 
shouting and shaking, analgesia is already present. This analgesia, 
developing before complete abolition of the consciousness, may be 
utilized for the performance of many minor operations. 

Some time after the complete abolition of the cerebral functions 
the reflex centres in the cord become paralyzed, and with the disap- 
pearance of the reflexes the muscle tone is also abolished, so that the 
anaesthetized patient lies completely relaxed, motionless, and without 
sensation. A stage, named by some the stage of toleration, by others 
the stage of surgical anaesthesia, has now been reached. Among the 
reflexes the last to disappear is the corneal reflex, whose disappear- 
ance, as is well known, is the signal for the surgeon that the further 
administration of the anaesthetic should be limited. Even in complete 
anaesthesia, the pupils should remain contracted, their gradual dilata- 
tion indicating an insufficient respiration, while their sudden dilatation 
is a sign of imminent danger to life. [As the pupils also dilate during 
recovery' from the anaesthetic, their dilatation may also be an indica- 
tion of this. — Tr.] 

As a rule, in chloroform anaesthesia the pulse is but slightly slowed, 
and after a time the face becomes pale. Marked retardation of the 
pulse to 50 beats or less per minute and extreme pallor are signs of 
a dangerous impairment of the circulation. In ether anaesthesia, on 
the contrary, the face remains flushed and the pulse is usually some- 
wli.il accelerated. [If before operation the pulse has been abnormally 
rapid, it very frequently is distinctly slowed and strengthened. — Tr.] 
In complete anaesthesia with ether or chloroform the respiration 
should be somewhat slowed, but should be regular and sufficiently 
deep. 

Influence on Motor and Sensory Functions. — The mere surface 
picture of anaesthesia shows that the sensibility of the cerebral cortex 
is abolished before the motor functions, perception of pain and touch 
being abolished al a stage in which the consciousness is still filled with 
dreams which cause active movements. The observations of Hitzig 
have clearly demonstrated this difference in the susceptibility of the 
Bensory and motor functions of the cortex. 

During his experiments in stimulation of the cerebral cortex, this author 
found thai 1 1 1 * - irritability of the motor portion of the cortex was abolished 

only during very deep ether narcosis. " Kvcn when every trace of reflexes 



58 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

had disappeared, when even the most intense sensory stimuli, such as those caused 
hy pulling on the dura or by strong induction currents in the nasal mucous 
membrane, no longer produced any reflex effects whatever, some of the motor 
centres still reacted to local stimulation." For the pharmacologist it is an 
interesting fact that while ether is finally able to prevent any effects from 
stimulation of the cerebral cortex, Hitzig found that morphine never weakened 
the effects of such stimulation, even when very large doses were administered 
intravenously. This clearly demonstrates the fundamental difference between 
the action of chloroform and ether and that of morphine on the motor tracts. 

Bernstein has shown that the spinal cord of the frog behaves in the same 
fashion as the cerebral cortex. This author, by stoppage of the blood flow through 
the lower portion of the spinal cord, protected this portion of the cord from the 
action of chloroform present in the blood, and found that the motor organs in 
the poisoned portion of the cord were, under these conditions, able to react to 
stimuli reaching them from the lower unpoisoned portion although the sensory 
receptive organs in the upper poisoned portion were already completely inex- 
citable. 

It therefore appears that everywhere in the central nervous system 
the motor organs become narcotized much later than the sensory ones. 
It is significant, in this connection, that the respiratory centres, which 
maintain the respiratory movements long after any reactions to sen- 
sory stimuli have ceased to occur, are automatic motor centres. 

Many facts indicate further that the motor centres experience 
an augmentation of their excitability before they are depressed by 
these anaesthetics. Krapclin, in psychophysical experiments, was able 
to demonstrate a facilitation of the inauguration of motor acts during 
the earlier phases of the alteration of the consciousness produced by 
ether and chloroform, while, on the other hand, perception was retarded 
from the start. It therefore appears that these two phases of mental 
activity, the perception of external impressions and the motor inner- 
vation, are influenced in opposite fashions, just as is the case during 
the earlier stages of the action of alcohol. 

This close relationship in the psychical effects of alcohol and of 
small doses of ether is also expressed by the fact that ether too pro- 
duces a distinct euphoria, which fact accounts for the occasional occur- 
rence of the chronic abuse of ether (Ewald). It is stated that in 
Ireland ether drinking is a comparatively wide-spread vice. 

The excitability of the peripheral nerve-trunks is certainly at first 
markedly augmented by the local action of chloroform or ether, this 
effect being followed by a depression and finally by the abolition of 
their excitability if they are further exposed to the action of these 
vapors (Bernstein, Waller and Bethe) . 

The primarily stimulating effect of ether and chloroform, like that of 
alcohol, occurs also in vegetable cells, Elfving having found the respiration of 
plants to be increased by these drugs, while, according to Kegel, they also increase 
the assimilation of C0 2 . 

"While the narcotic actions of ether and chloroform on the cerebrum 
differ from each other only quantitatively, when, disregarding their 
anaesthetic actions, we investigate the disturbances and alterations of 



ANAESTHESIA 59 

function which occur during anaesthesia, we find, very essential differ- 
ences in the actions of these two most widely used anaesthetics. 

Certain disturbances occurring during anesthesia are merely 
mechanical results of the muscular relaxation, — for example, the 
interference with respiration and asphyxia, occasioned by the tongue 
falling back on the larynx, and the interference with the power of 
swallowing, which may cause aspiration pneumonia. Another frequent 
disturbance, particularly at the start, is vomiting, which is probably 
of central causation, and not due to the local irritating effects of the 
anaesthetic which may be swallowed with the saliva. [The local irritat- 
ing effect in the pharynx doubtless at times plays a role in producing 
such vomiting, and it also seems to the translator that the local 
irritating effects, especially of ether, in the stomach, which frequently 
appear to cause a free secretion of hydrochloric acid, cannot be disre- 
garded as a probable contributory cause of the nausea and vomiting 
which follow the recovery from the anaesthetic. — Tr.] 

Annoying Reflexes. — When the vapor of ether or chloroform is 
inhaled, there occur a number of reflexes, just as is the case after 
the inhalation of other irritating gases, which reactions may be con- 
sidered to be, as it were, defensive in their nature, by the aid of which 
the organism endeavors to guard the respiratory tract from the 
entrance of irritating vapors. Especially in experiments on ani- 
mals there occurs with great regularity a stoppage of the respiration 
in the phase of expiration, or violent expiratory efforts and convulsive 
closure of the pharynx, which are due to reflexes originating in the 
nasal mucous membrane as a result of the irritation of the terminations 
of the trigeminus (Kratschner) . The more concentrated the vapors 
inhaled, the more well developed is this reflex. After a short period, 
this stoppage of the respiration passes off, and the breathing then 
continues regularly and deeply (see Fig. 4). Simultaneously with 
this inhibition of the respiration, there often occurs a very pronounced 
slowing of the pulse, which also is reflexly induced, and at times the 
heart may cease to beat temporarily. [This reflex inhibition of the 
heart would appear to be a contributory cause of death in some cases 
of sudden death at the very commencement of chloroform anaesthesia. — 
Tr.] 

In man these reflexes produce slighter effects than in the rabbit 
or in the cat, and consequently, if one commences the anaesthetization 
rory gradually, administering such slight concentrations of the anaes- 
thetic that they produce only slight irritation, and if this concentra- 
tion be only gradually increased, as a rule these disturbing reflexes 
may be completely avoided, for the reflex centres will be sufficiently 
narcotized to prevent their reaction to the irritation caused when the 
concentration of the inhaled ana i sthetic is great enough to produce its 
local irritating effect in the upper air-passages. 

The first effects on the respiration produced by the anaesthetic 



60 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

after its absorption are an acceleration and deepening of the respira- 
tory movements, which may be best observed in vagotomized subjects, 
for with intact vagi the reflex effects originating in the pulmonary 
nerves complicate the picture. Knoll * and Cushny go so far as to 
assume a primary excitation of the respiratory centre. In the stage 
of surgical anaesthesia the breathing, which during the stage of excite- 
ment was irregular, becomes regular and slightly slowed, and, as the 
sensibility is abolished, the respiratory centre is no longer affected by 
any reflexes, even long before it is itself depressed (Cushny). If the 
narcosis is pushed beyond the necessary stage, a final stage follows in 
which the breathing either gradually becomes shallower and shallower 
and finally stops entirely, or, but much less frequently, stops more or 
less suddenly. In general, observations on animals indicate that the 
respiratory centre resists the action of full anaesthetizing doses of ether 
longer than it does those of chloroform, and the practical experience 
of surgeons demonstrates that asphyxia occurs much less frequently 
with ether than with chloroform. 

ACTION ON THE CIRCULATION 

Vasomotor Centres. — There is a much greater difference between 
the two anaesthetics in respect to the intensity of their effects on the 
vasomotor centres and the heart. The vasomotor centres controlling 
the cutaneous vessels, and particularly those of the face, are, from 
the start, particularly depressed by ether and chloroform, and conse- 
quently at the start of the narcosis the face becomes flushed. When 
chloroform is inhaled, however, as a rule, the blood supply to the skin 
diminishes as the anesthesia becomes deeper, because other vascular 
systems lose their tone and, as a consequence, the blood leaves the skin 
to go to these other regions. "With ether, on the contrary, the face 
usually remains flushed, for the vasomotor centres controlling other 
vascular systems are much less affected by it than by chloroform. 

Chloroform depresses the vasomotor centres far more than does 
ether, so that, even when chloroform anaesthesia is cautiously induced, 
the blood-pressure falls decidedly, while when ether is used it may 
for a long time remain at the normal level. In animal experiments 
this difference may be strikingly demonstrated if the animals are 
anaesthetized with doses of these two anaesthetics which are just suffi- 
cient to induce anaesthesia. While it is true that if the chloroform 
concentration of the blood is very gradually inci-eased so that complete 
anaesthesia is induced only after 30-35 minutes of absolutely regular 
administration of the anaesthetic complete insensibility and complete 
abolition of the reflexes may be obtained without inducing any fall in 
the blood-pressure, with the continued maintenance of the same degree 
of anaesthesia the blood-pressure falls slowly and progressively, so 
that after about an hour it may be reduced to one-half of the normal 
height and after 2% hours to one-third, while the respiration may 



THE CIRCULATION DURING ANAESTHESIA 



61 



62 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

continue regularly and normally (Rosenfeld). Such experiments 
indicate that the circulation is markedly impaired even by very 
cautiously conducted chloroform anaesthesia and relatively much more 
markedly than is the respiration. On the other hand, if ether be 
administered cautiously, complete anaesthesia is readily induced with- 
out causing any change in the blood-pressure, and even when the 
anaesthesia is continued for hours the carotid pressure need fall but 
slightly. In fact, if during a chloroform anaesthesia the blood-pressure 
has been caused to fall slowly and progressively and ether be substi- 
tuted and the anesthetization continued with it, the blood-pressure 
Avill gradually rise once more. 

In man the same holds true. Blaiiel, using Gartner's tonometer, 
found that in 100 ether anaesthesias of average duration the blood- 
pressure remained above the normal throughout, while in 37 chloro- 
form anesthesias it was regularly below the normal level. 

Thus far the fall in blood-pressure during chloroform narcosis 
has been represented as the result of a depression of vasomotor centres, 
but without any presentation of proof that this is so. It is, however, 
clear that a gradual diminution in the power of the heart must also 
cause a fall in the blood-pressure, and earlier investigators have attrib- 
uted this without question to a weakening of the cardiac action. 
Scheinesson 2 was the first to observe vasodilatation in the rabbit's 
ear during anaesthesia, which he attributed to depression of the vaso- 
motor centres. In the rabbit, after section of the vasomotor nerves of 
one ear, the inhalation of chloroform causes a dilatation only of the 
vessels of the other ear whose nerves are still intact (Knoll 2 ), and 
consequently it is evident that this vasodilatation is caused centrally. 
The acceleration of the blood flow from a mesenteric vein observed 
by Pick indicates that, when the vessels are relaxed during chloroform 
narcosis, the blood collects chiefly in the vessels of the lower abdomen. 
A similar depression of the vasomotor centres is caused by ether in a 
much slighter degree and only by much larger doses. 

Action on the Heart. — It is very possible that in the usual chloro- 
form narcosis, in addition to the vasomotor depression, a weakening 
of the heart action is also responsible for the gradual fall in blood- 
pressure, for, as will soon be discussed more fully, chloroform is a 
powerful cardiac poison in concentrations which are but slightly higher 
than that necessary for the induction of anaesthesia, and consequently 
even slighter concentrations may well produce such effects when acting 
on the heart for a considerable period. However, at the start the fall 
in blood-pressure is chiefly due to the depression of the vasomotor 
centres. This may be concluded from the fact that it is possible by 
very slowly increasing the amount of chloroform in the blood to cause 
complete paralysis of the vasomotor centres while the heart still 
continues to beat relatively well. Under such conditions the vasomotor 
centres are found to be completely insusceptible to stimulation by even 



CHLOROFORM A CARDIAC POISON 63 

the most powerful stimuli, such, as asphyxia or a sudden anaemia 
produced by ligating all the arteries passing to the brain, although at 
this time the moderately slowed but powerful heart-beats are still 
able to maintain the blood-pressure at a level corresponding to that 
observed after the complete relaxation of the vessels which follows 
section of the cervical cord. 

The greater the concentration of the chloroform in the blood, the 
more evident does its action on the heart become. As a consequence, 
irregularities in the heart-beat may often be noted early in a chloro- 
form anaesthesia, for the percentage of chloroform in the blood neces- 
sary for the maintenance of a satisfactory anaesthesia — according to 
Pohl on an average 0.035 per cent. — is sufficient to weaken the heart 's 
action, as shown by Sherrington and Sowton in their experiments 
on surviving mammalian hearts perfused with blood containing 
chloroform. 

Moreover, without any direct participation of the heart, the results 
of the general vascular relaxation are dangerous enough, for, as the 
blood collects in the splanchnic vessels, the other portions of the body 
receive but little blood, the face of the anaesthetized subject becomes 
pale and his skin cold, while the pulse becomes weak, and collapse 
may occur during the anaesthesia. 

Of greater practical importance than this gradual fall in the 
blood-pressure, occurring when chloroform is pushed too far, is the 
sudden cessation of the cardiac activity, which may occur if too large 
quantities reach the blood at one time. With ether this danger is 
far less imminent, for the difference in the concentration of the drug 
which is sufficient for anaesthesia and that which causes cessation of 
the heart's activity is much smaller with chloroform than with ether. 
This is, from the practical point of view, the decisive difference 
between these two anaesthetics. 

Chloroform a Cardiac Poison. — The earlier investigators also 
noticed that chloroform impaired the activity of the heart, Snow, 
as early as 1852, having observed that the vapor of chloroform when 
directly applied to the exposed heart stopped its beating. Later, 
8ch iiicsson 1 demonstrated that the cardiac activity was impaired by 
the inhalation of chloroform, and numerous later experiments in which 
various methods were employed have brought further proof that this 
is so.* 

Newer experimental methods have rendered it possible to demon- 
strate in the most complete fashion the harmful effect of chloroform 
on Hie isolated mammalian heart. While these methods will be more 

•Among others, mention should ho made of the interesting experiments of 
(Itisl.i II and Shore in which, with the aid of a cross-circulation between two ani- 
mals, the blood containing chloroform acted in one only on the central nervous 
system, while in the other it acted only on the heart. In these experiments the 
blood-pressure always fell when the blood containing the chloroform reached the 
heart. 



64 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

fully discussed in the chapter on the Pharmacology of the Circulation, 
their results are briefly given here. Bock, making use of an experi- 
mental method in which the blood-pressure depends exclusively on the 
work done by the heart, has shown that the inhalation of chloroform 
mixed with air is immediately followed by a fall in the blood-pressure 
and that the heart-beats are slowed independently of any action on the 
central nervous system, while the inhalation of strong ether vapor, 
even when continued for a considerable period, alters the blood-pressure 
and frequency of the heart-beats but slightly. 

By experiments on artificially perfused hearts it has been possible 
to determine quantitatively the great difference in the action exerted 
on the heart by these two anaesthetics. Those conducted by Dieballa 
on frogs' hearts, and numerous more recent experiments conducted 
on surviving mammalian hearts, have demonstrated that the molecular 
concentrations of chloroform and ether which produce death of the 
heart are in the proportion of 1 to 30-35. Pohl found 0.058 per 
cent, of chloroform in the blood contained in the left ventricle of a 
dog which had been narcotized until the heart stopped.* As, accord- 
ing to this author, the concentration of chloroform in the blood when 
the narcosis is deep, but while the heart is still beating well, is on the 
average 0.035 per cent., and according to Niclo-iix 0.05 per cent., 
these figures show conclusively how slight the difference is between 
the concentration necessary for the maintenance of anaesthesia and 
that which causes paralysis of the heart. Here we find the explanation 
of the cases of sudden heart death which occur during chloroform 
anaesthesia. With ether such cases do not occur. 

Cardiac Death in Chloroform Narcosis. — In order clearly to 
understand the danger to which the heart is exposed by the adminis- 
tration of concentrated chloroform vapor, one must remember that 
with incautious dosage the heart is the first organ to be imperilled. 
In a sense we are dealing with a local action of the chloroform-laden 
blood on this organ, for the blood which contains the largest amount 
of the anaesthetic flows directly into the heart, and only later is the 
anaesthetic distributed around in all portions of the circulation. The 
heart can therefore be very seriously poisoned by the sudden entrance 
into it of blood containing too much chloroform, even before any 
general narcosis has developed. If by such abrupt administration 
of chloroform the action of the left ventricle is markedly weakened 
for even a short time, a vicious circle is produced, which with each 
instant augments the damage suffered by the heart, for, as the heart 
empties itself but incompletely, it is directly exposed to a persisting 

* In one case in which Pohl had forced air saturated with chloroform into 
the lungs and in which immediate heart death occurred, as much as 0.22 per 
cent, was found in the blood contained in the heart. However, in this case it 
is highly probable that a great excess of chloroform entered the blood during the 
last respiration. 



CARDIAC DEATH FROM CHLOROFORM 



65 



poisonous action of the blood stag- 
nating in it and containing poison- 
ous amounts of chloroform, and 
consequently the continuation of this 
condition results in death of the 
heart. This is the reason why, when 
the heart is suddenly paralyzed by 
too large doses of chloroform, it is 
no longer possible to revive it by 
ceasing the administration of the 
drug and inaugurating artificial 
respiration. Under such conditions 
it may be revived only if this blood, 
which is saturated with chloroform, 
be removed from the heart, which 
may be accomplished by compression 
of the thorax, and in case of need 
by the intravenous (or intracardiac) 
administration of epinephrin 1 to 
100,000 (see chapter on Circulation) 
[or by transdiaphragmatic massage 
of the heart, which has already under 
such conditions been the means of 
saving a considerable number of 
lives.— Tr.] 

As is to be expected from the 
manner in which it occurs, chloro- 
form heart death presents a materi- 
ally different appearance from that 
of death due to vasomotor paralysis. 
This may be readily demonstrated 
in the laboratory by compelling 
an animal to inhale all at once large 
quantities of chloroform, in which 
case the blood-pressure falls more 
Or l<ss suddenly and the cardiac 
pulsations disappear completely. 
After cessation of the circulation, 
however, several respiratory move- 
ments occur, and in fact convul- 
sions due to asphyxia may occur 
j'lsl ;k in any other sudden stop- 
page of the circulation. In this 
case the stoppage of the heart 
puts an end to life before deep 
narcosis has been attained. (See 
Fig. 6.) 

5 




66 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Many eases cited in the literature, in which death has occurred 
after a few inhalations of chloroform, were certainly due to such sud- 
den overloading- of the blood with chloroform as a result of careless 
pouring on the mask of too large amounts of the anaesthetic. The 
comment often made in such cases, that death could not have been 
due to administration of too much chloroform because not enough 
had been given to produce narcosis, is only explainable by the fact 
that the observer had thoroughly misunderstood the true cause of 
death. 

Analysis of the Causes of Experimental Chloroform Death. — In 
considering the evidence which has been furnished by animal experi- 
mentation, in regard to the causes of death by chloroform, it is seen 
that two forms may be distinguished. With the gradual absorption of 
too large quantities of chloroform, all the organs succumb to the 
poison in fairly equal degree, and the abolition of the functions of 
the different portions of the central nervous system occurs in the 
order of their relative susceptibility. As the vasomotor centre suffers 
very early, a stair-like fall in the blood-pressure results from the 
general vascular paresis, and finally the respiration fails, death result- 
ing from the cessation of the breathing, although the heart continues 
to beat regularly and with a fair degree of force. The heart is conse- 
quently the last to die in this form, which resembles the usual death 
occurring in ether narcosis. In the other form, large amounts of 
chloroform pass rapidly into the blood and paralysis of the heart 
results, and, as the poisoned heart is unable to expel this blood, which 
is saturated with large amounts of chloroform, from its cavities and 
vessels, actual death of the heart quickly follows the paralysis. In this 
form of chloroform death, the respiration continues after the heart 
has ceased to beat. 

As in practice intermediate forms between, and combination forms of, these 
two occur, the consequent varying course and appearance of fatal chloroform 
accidents have led to an active discussion as to whether death in chloroform 
narcosis is due to respiratory or cardiac paralysis. Particularly the Paris 
Commission of 18.55, the English Commission of 1864, and the two Indian Com- 
missions of 1889 and of 1890, have, by means of numerous experiments on 
different species c.f animals, firmly established the fact that a proper adminis- 
tration of not too concentrated chloroform vapor, if persisted in, always 
results in the respiration stopping first, while the heart continues to beat for 
some time — 2 to 12 minutes — longer. On the other hand, other authors have 
repeatedly emphasized the fact that death may also result from a primary 
stoppage of the heart (Scheinesson, 1 , 2 Schmey, Cushny, Ratimoff, and others), 
From what has been said above, these contradictions in the experimental 
results are readily explained by the variations in the experimental conditions. 

Chloroform Death in Man. — Actual experience with chloroform 
death in man agrees with the experimental data, except that in man 
one often is dealing with individuals whose hearts have already been 
weakened by degenerative changes. Among the autopsy findings after 
sudden death from chloroform, very frequently fatty degeneration 



DEATH FROM CHLOROFORM 67 

of the heart is noted. Consequently it is easy to understand why in 
man death due to the heart should occur with relatively greater 
frequency than is the case in experiments on animals. 

If the chloroform accumulates in gradually increasing amounts in 
the blood, extreme pallor of the face and cyanosis develop, as expres- 
sions of the fact that the vasomotor and respiratory centres have 
become incapable of performing their functions, and asphyxia occurs 
while the heart continues to beat. If in such cases artificial respiration 
be instituted promptly enough, the natural respiratory movements, 
as a rule, start up again as soon as the excess of chloroform has been 
eliminated. However, cases do occur in which the respiration does not 
return although the heart clearly continues to beat for some time 
longer. 

Nothnagel and Rossbach mention such a case in which artificial respiration 
was carried on in a most efficient fashion for half an hour, as long as the heart 
continued to beat, without any reappearance of the voluntary respirations. Quite 
characteristic of such irreparable respiratory paralysis in the presence of a 
heart which continued to beat well, is the description of Jenop's case of a man, 
aged 48, to whom chloroform was to be administered on account of the amputation 
of a finger. " The patient was more restless than usual and was completely 
anaesthetized after the administration of not more than two drachms of chloro- 
form. The operation was about to start, when he snorted two or three times, 
suddenly became blue in the face and ceased breathing, while the radial pulse be- 
came very weak. The heart sounds were audible for 20 minutes longer, during 
which time no visible respiratory movements occurred." All attempts at revival 
were unsuccessful. Post-mortem examination disclosed nothing of any particular 
moment. 

If the face of the chloroform patient suddenly becomes pale, the 
pupils dilate and become fixed, the pulse disappears, and the heart 
ceases to beat, while the respiration continues for some time, the pros- 
pects for revival are much less favorable. This is the picture seen 
in heart death due to sudden overloading of the pulmonary blood 
with chloroform. Such accidents occur usually at the commencement 
of the ana-sthesia, when the patient is violently excited and the anaes- 
thetist attempts to attain surgical anaesthesia too rapidly, or, with an 
excited patient, endeavors to control him by incautiously pouring too 
much chloroform on the mask. From many typical reports of such 
eases, the following may be cited from Schmey: 

For the purpose of removing a gland from the submaxillary region in a 
man of I-"' years, anaesthesia was started. "At the very start, however, when only 
a f.w cubic centimetres of chloroform had been poured on the mask, the patient 
Buddenly became pulseless, but continued to breathe quietly and deeply several 
times more. Artificial respiration was instituted, and a pulsation in Ihe radial 
artery could be clearly felt each time pressure was made oil the thorax. If 
then the artificial respiration was Btopped, natural breathing was continued for 
a short, time, but no spontaneous pulse in the radial artery could be felt. Arti- 
ficial respiration was instituted again with the same effect, and this was con- 
tinued for longer than an hour with similar results.*' The autopsy disclosed 
marked fatty degeneration of the heart. 

In many cases of death occurring a1 the start of the anaesthesia, 
death has been attributed to the effects of shoe!,-, and eases certainly 



68 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

vouched for (Xussbaum) do in fact demonstrate that, under similar 
circumstances of marked excitement in especially feeble persons, car- 
diac death may result from varying sensory stimuli without any 
anaesthetic whatever having been administered. It is not inconceiv- 
able, consequently, that the first inhalations of the irritating vapors of 
chloroform or ether may cause death through their reflex effects on the 
respiration and the heart without there being any question of an over- 
dose having been administered. However, these reflex effects which 
have been mentioned before, the stoppage of the respiration in expira- 
tion and the inhibitory stoppage of the heart, are much less pronounced 
in man than in animals and pass off rapidly. It is very improbable that 
they play any important role in the accidents of anaesthesia, especially 
as these reflex effects are by no means slighter when ether is inhaled 
than when chloroform is administered, and yet such accidents occur 
more frequently with the latter anaesthetic. In any case, especially 
if the narcosis be gradually induced, the reflex inhibition of the heart 
may be certainly prevented by previously administering atropine 
(y 2 mg.) and the marked reflex effects on the respiration by that of 
morphine (0.01-0.2 ! gm.). 

AvoidabiUty of Anaesthetic Accidents. — The foregoing discussion 
of the dangers to the respiration and circulation which attend anaes- 
thesia shows clearly that the boundary between sleep and death in deep 
narcosis is small enough. However, at the same time our knowledge 
of the causes of these dangers makes it equally clear that, in the great 
majority of cases, these accidents may be avoided, for they are practi- 
cally always the results of a faulty management and incautious dosage 
of the ancesthetic. 

The anaesthetic methods of the day are very susceptible of an 
improvement which would permit of an exact and reliable means of 
varying and controlling the degree of narcosis produced. However, 
even with the methods usually employed at the present time, it is pos- 
sible to avoid these dangers if the anaesthetist understands the condi- 
tions controlling the absorption and elimination of the anaesthetic 
and is thus in a position to appreciate correctly the causes of these 
possible dangers. 

Laws Governing the Absorption and Distribution of Anaes- 
thetic Gases. — The absorption of chloroform or ether vapors by the 
blood depends on the plasma's coefficient of absorption for these gases 
and on the temperature and the partial pressure of the anaesthetic in 
the alveolar air. As the absorption coefficient at body temperature 
niay be considered as constant, the absorption of chloroform or ether 
at any instant is directly proportional to the partial pressure of the 
anaesthetic in the inspired air, — i.e., to its volume per cent. 

It goes without saying that the more the functional nervous ele- 
ments are permeated by the anaesthetic the more pronounced will be 
its action on the nervous system. The distribution of chloroform or 
ether throughout the organism follows certain well-defined laws, the 



ABSORPTION AND DISTRIBUTION OF ANESTHETICS 69 

cells of all tissues, and especially those of the nervous system, having 
a greater affinity for them than has the plasma. The cause of this 
unequal partition of the anaesthetic between the nutrient fluid and the 
cellular elements has been found, as will be more fully discussed later, 
to lie in the greater power to dissolve chloroform with which the cells 
are endowed on account of the presence in them of fat-like or lipoid 
substances such as cholesterin, lecithin, etc. According as the cells 
in different regions contain larger or smaller amounts of such lipoids, 
they absorb larger or smaller quantities of chlorof orm. In consequence, 
therefore, of their greater power of dissolving the anaesthetic, the 
tissues absorb it in greater concentration from the blood, and conse- 
quently, at the commencement of every narcosis, the blood returns to 
the right heart from the systemic circulation containing less chloro- 
form than is carried to the tissues from the left heart. According to 
Xicloux's analyses, venous blood of dogs, even when full anaesthesia 
has been maintained for a considerable period, contains on an average 
0.05 per cent, of chloroform while the arterial blood contains 0.06-0.07 
per cent. At the commencement of anoesthetization this difference is 
naturally much greater, and consequently when the anaesthetic is 
administered incautiously the left heart is much more exposed to 
danger than is the right. For example, Pohl found 0.22 per cent, 
of chloroform in the blood of the left ventricle but only 0.02 per cent, 
on the right side in a dog in which he had brought about a sudden 
cardiac death by the rapid administration of air saturated with 
chloroform. Such are the conditions in those cases in which the 
overloading of the blood in the lungs with chloroform may poison the 
left heart before the chloroform is sufficiently distributed and absorbed 
by 1 lie other tissues and consequently before any narcosis develops. On 
the other hand, when a properly induced anaesthesia is at its height, the 
central nervous system contains relatively more chloroform than does 
the blood. 

Bowever, the tissues are never able to remove all the chloroform 
from the blood. On the contrary, with continuous inhalation a condi- 
tion of equilibrium between blood and tissue cells must gradually 
tablished, which corresponds to the distribution coefficient of the 
solubility of the chloroform in the blood fluid and in the body tissues. 
When, on the other hand, further administration ceases and the 
elimination through the Lungs commences, so that the concentration in 
the blood diminishes, it necessarily follows that the chloroform moves 
in the reverse direction, from the tissues back into the blood. Naturally, 
with persisting elimin.it ion the normal functions are again established. 

These phenomena may be compared Avith extraction by agitation 
when ;i substance less Boluble in water than in another fluid, used as an 
extractor, distributes itself between the two fluids and, in accordance 
with its greater solubility in the second fluid, accumulates in larger 
quantities therein, and yet may be removed from this fluid again if 
repeatedly extracted with pure water, in the body, chloroform at 



70 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

each moment distributes itself between the blood and tissues in 
accordance with its relative solubility therein, just as occurs in the 
method of extraction by shaking. 

The amount of chloroform present in the central nervous system 
is consequently always proportional to the amount present in the blood 
supplying this organ. Step by step it follows the chloroform partial 
pressure as it rises or falls in the blood. The amount of chloroform 
present in the blood is, however, for its part also dependent in an 
entirely similar fashion on the chloroform partial pressure in the 
inspired air, — i.e., on the volume per cent, of its vapor in the alveoli. 
The depth of narcosis consequently is increased or diminished in 
direct proportion to the concentration of the anaesthetic in the air 
inspired. 

The various events and happenings in anaesthesia thus occur in the 
following fashion. 

In the lungs there occurs an exchange between the blood and the 
inspired air in which, with a given concentration of chloroform in the 
air, the blood absorbs from it a certain portion, and consequently at 
the start less of the anaesthetic is contained in the expired than in the 
inspired air. For example, Harcourt found 0.55 per cent. CHC1 3 in 
the inspired air but only 0.34 per cent, in that expired at this time, 
this showing that the blood had given up a considerable portion of its 
chloroform to the tissues. This continues until a condition of equilib- 
rium has been established between the chloroform content of the blood 
and that of the tissues. In the meantime, so long as the blood returns 
to the lungs from the tissues poorer in chloroform than when it left 
them, it must compensate for this loss by absorbing chloroform from 
the alveolar air until the chloroform tension of the blood and the 
alveolar air is equalized. With the inhalation of a mixture with 
constant chloroform content, there is a constant flow of chloroform 
from the inspired air to the blood and from this to the tissue cells 
until the chloroform tension of the tissues and of the blood has become 
equal to that of the air inspired. When this state has been attained, 
the percentage of chloroform in the blood and in the tissues remains 
unchanged as long as the amount of the chloroform in the air respired 
remains constant. If the chloroform content of the air breathed be 
increased, the same play as formerly repeats itself, more chloroform 
being taken up by the blood and consequently more being absorbed 
by the tissues from the blood until the partial pressure of chloroform 
in the tissues, in the blood, and in the alveolar air has again become 
equal.* 

If the administration of chloroform ceases entirely, the blood at 
the start gets rid of the chloroform very rapidly, and, corresponding 

* Recent analyses by Nicloux give 0.05 per cent, of chloroform and 0.13-0.14 
per cent, of ether as average figures for the amounts of these substances present 
in the blood during deep anaesthesia. 






RECOVERY FROM ANESTHESIA 



71 



to its lessened tension in the blood, chloroform rapidly passes from the 
tissues into the blood and thus starts a current in the opposite direc- 
tion, — i.e., from the tissues through the blood to the expired air. If 
the air inspired contains no chloroform, the chloroform contained 
in the nervous system after a short time becomes so diminished that 
it is no longer sufficient to maintain narcosis, and the patient wakes 
up. The last portions of the chloroform, however, are relatively slowly 
eliminated, for the tissues possess a much stronger affinity for the 
drug than that of water. This gradual diminution of the chloroform 
present in the blood of anaesthetized dogs is illustrated in the following 
table of Nicloux, in which it may be seen that chloroform may be 
recognized in the blood even seven hours after discontinuation of its 
administration. 



Chloroform Content 


of Blood after Termination 


of Anaesthesia. 




Per cent, of chloroform in blood 


of anaesthesia 


Exp. 1 


Exp. 2 




0.054 

0.0255 

0.0205 

0.018 

0.0135 


0.0595 












0.023 




0.018 




0.0075 


7 hours 


0.0015 







The elimination of ether from the blood takes place somewhat more 
rapidly, which explains the more rapid recovery from ether narcosis. 



Ether Content of Blood after Termination of Anaesthesia. 





Per cent, of ether in blood 


of anaesthesia 


Exp. 1 


Exp. 2 


<i minutes 


0.115 

0.071 
0.063 
0.052 
0.025 


0.159 




108 




0.080 




0.05S 


1 hour 


0.021 


2 hours 


0.004 







Laws Governing Dosage. — The symptoms in narcosis make it clear 
that a certain degree of saturation of the tissiics with the anaesthetic 
i om s ponds to every variation of the partial pressure of the gas in the 
alveolar air. The depth of the ancesthesia is consequently at every 
nimni nl dependent on the partial pressure of the ancvsthctic in the gas 
mix fun n spired. 



72 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

From this law, first propounded by the French physiologist P. Bert, 
follows the — for the management of anaesthesia — extremely important 
conclusion, that the depth of the narcosis and the danger thereof is not 
at all dependent on the absolute amount of the anaesthetic which has 
been used, but upon the concentration of the anaesthetic in the air 
respired. The control and modification of the degree of action, which 
with non-volatile drugs is attained by modification of the absolute 
size of the dose, is, during the administration of gases, attained by 
modification of the concentration administered. Consequently in every 
moment of the anaesthesia a sufficient dilution of the anaesthetic with 
air is an essential condition. 

"With anaesthetics, just as with non-volatile drugs, the therapeutic 
and toxic doses must be determined. With them it is necessary to 
establish the concentrations which produce a safe anaesthesia of suffi- 
cient depth, and one which may be maintained for some time without 
injury, and to find out at which concentrations the dangerous accidents 
may occur. The therapeutically efficient and toxic concentrations 
represent the limits for safe depth of anaesthesia. Paid Bert called this 
interval the "zone maniable. " 

Since the time of Bert many experiments, and in recent times 
with methods free from objections, have been undertaken in order to 
determine the therapeutically effective and the toxic concentrations of 
chloroform and ether, and the figures obtained agree closely enough 
for practical purposes. Bert V found 1.5 volume per cent, of chloro- 
form vapor in the inspired air sufficient to produce narcosis, but this 
figure is too high, for Kionka ~ found that the concentration suitable 
to induce and maintain narcosis lies between 0.6 and 1.2 volumes per 
cent. 

The following table gives the results of Rose nf eld's 1 experiments in 
which he investigated the intensity of the action produced in rabbits 
by different mixtures of air and chloroform ; 



Relationship between the Percentage of Chloroform and Ether in the Respired Air and 
the Depth of the Anaesthesia (Rosenfeld, Spenzer). • 



Chloroform, percent- 
age by volume 


Time necessary to in- 
duce anaesthesia 


Depth of anaesthesia 
or narcosis 


Remarks 


0.54-0.69 

0.96-1.01 

1.16-1.22 


2hrs 

30-40 min 

30 min 


No narcosis 

Complete 

Complete 

Deep 

Deep 


Only somnolence. 

Blood-pressure at first 
normal then gradual 
fall for 4 hrs. Res- 
piration normal. 

Cessation of respiration 
at end of 2 hrs. 

As above after 1 hr. 

As above after 30 min. 


1.41-1.47 

1.63-1.65 


37 min 

12 min 



DOSAGE OF ANESTHESIA 



73 



Relationship between the Percentage of Chloroform and Ether in the Respired Air and 
the Depth of the Anaesthesia (Rosenfeld, Spenzer) — Continued. 



Ether, percentage 
by volume 


Time necessary to in- 
duce anaesthesia 


Depth of anaesthesia 
or narcosis 


Remarks 


1.5 


2 hrs 


Hardly any 

Very incomplete . . 
Complete 

Complete 


Only slight somnolence. 


2.5 




3.2-3.6 




Respiration and car- 
diac function re- 
mained good for 
hours. 


4.45 




6.0 




regular; pulse accel- 
erated. 
Respiration ceased in 
8-10 minutes. 









As may be seen from this table, for rabbits the efficient dose of 
ether lies between 3.5 and 6.0 per cent, by volume. In man similar 
concentrations are sufficient, as shown by Dreser, 1 who, at the height 
of deep ether narcosis, collected air from under the mask and found 
in it on the average 3.7 .per cent, by volume. 

It is thus seen that a concentration of about 1 per cent, by volume 
of chloroform vapor is sufficient to maintain a complete anaesthesia 
in the rabbit, even for as long as four hours, with the respiration 
remaining normal and the blood-pressure falling only very slowly. 
However, anaesthesia is induced only very slowly with this low and 
consequently safe concentration. A concentration only slightly higher 
— for example, 1.6 per cent. — induces anaesthesia much more rapidly, 
but with this concentration the respiration may stop when its inhala- 
tion has been continued for half an hour. It is consequently clear that 
the limit of safety is much smaller for chloroform than with ether, and 
this difference in the size of the difference between the therapeutic and 
the toxic concentration of the two ancesthetics is merely the exact 
expression and explanation of the now generally accepted clinical con- 
clusion that chloroform narcosis is attended with a greater direct 
danger to life than is ether narcosis. The comparison of the figures 
for the concentrations necessary for the induction of anaesthesia shows 
further that ivith ether the percentage by volume present in the 
respired air must be at least three times larger than is the case with 
chloroform. 

A iter Dangers op Ether Narcosis. — In ether narcosis an over- 
dosage lasting for a short time is by no means so likely to produce 
din ( t disturbances of the circulation and respiration as is the case with 
chloroform. On the other hand, if the permissible concentration be 
exceeded, local irritant effects in the respiratory mucous membrane 
result. A mixture of air with 7 per cent, of ether vapor is quite 
irritant to the mucous membrane of the larynx and causes a reflex 



74 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

cough, and at times a temporary closure of the glottis, causing a feeling 
of suffocation (Dreser 2 ). However, these reflexes, which act, as it 
were, as sentinels to prevent the entrance of irrespirable vapors into 
the lower air-passages, soon cease if the ether inhalation is continued, 
and the sensibility is thus further depressed. These irritant actions 
affect at the start the mucous membranes of the mouth, the naso- 
pharynx, and the upper air-passages. The salivary glands especially 
are stimulated to active secretion, and, as the anaesthetized individual 
can neither expectorate nor swallow, mucus and saliva collect in large 
amounts in the mouth and throat. Rattling respiration results, and 
bronchitis or pneumonia may develop some time later. It is ques- 
tionable whether these inflammations are due to the direct irritation 
produced by the ether vapor in the tracheal and bronchial mucous 
membranes, or whether they result from the aspiration into the lungs 
of the saliva and mucus secreted so profusely (Grossmann, Hblscher, 
Elipstein) . A hypodermic of atropine or scopolamine preceding the 
ether narcosis will entirely prevent or markedly lessen this hyper- 
secretion. 

Chloroform anaesthesia also is followed by dangerous after 
effects if too high concentrations are administered, or even if the 
proper concentrations are administered for too long a time, fatty 
degeneration of the liver, of the heart, and of the kidneys developing 
under these conditions, all lesions which may be regularly demon- 
strated in animals after a single long-continued chloroformization of 
same {TJngar, Strassmann, Ostertag). They are due to a toxic action 
on the cells of these internal organs, which occurs along with the 
narcosis of the brain, but which is not dependent on the cerebral 
actions, for they may be caused by repeated subcutaneous injection of 
non-narcotic doses of chloroform, which produce similar lesions in 
the same organs {Nothnagel). The very intense fatty infiltration of 
the liver and of the heart, sometimes observed, is the expression of a 
very severe cell destruction ( Rose nf eld 2 u. Rubow). 

These experimental findings make clear the cause of those fatal 
cases in which, after chloroform anaesthesia, death occurs with the 
symptoms of serious liver disease or those of increasing cardiac weak- 
ness and coma (Bandler, Ambrosius, Fr'dnkel, Kast u. Blester). The 
harmful after-effects on the kidney are evidenced by the frequent 
appearance of albumin and casts in the urine (Rindskopf). In addi- 
tion, an increased destruction of proteid and the appearance in the 
urine of pathological decomposition products of proteids have been 
proved to occur (Kast u. Mester). 

After ether all these metabolic disturbances are by no means so 
pronounced as after chloroform. In particular, Selbach's experiments 
have shown that even long-continued and frequently repeated ether 
narcoses do not so readily cause the death of animals as do repeated 
chloroform narcoses. 

From what has been said it is evident that almost all of the dangers 






ANESTHETIC METHODS 75 

of anaesthesia are due to the administration of too high concentrations 
of the anaesthetics. With chloroform even a slight overdosage directly 
imperils life, while the after-effects of ether on the respiratory organs 
are usually due to the inhalation for a considerable time of ether vapor 
which is insufficiently diluted with air. 

Drop Method. — It follows that the drop method is the only one 
permissible for the administration of the more dangerous chloroform, 
for by this method the dosage may be physiologically varied, — i.e., 
may, according to the observation of the symptoms of the anaesthetized 
patient, be administered drop by drop, at times more rapidly and 
at times more slowly, when once the necessary depth of anaesthesia 
has been attained. 

In order to avoid the reflexes produced by too concentrated vapor, the 
administration should be started very gradually, at the rate of about 20 drops 
in the minute, this rate being gradually increased to, at the most, 60 drops 
in the minute, and, when surgical anaesthesia has been attained, the number of 
drops should again be diminished. On account of the lower boiling point of ether, 
it is much more difficult, when using the drop method and a loosely applied 
mask, to produce the concentration of the vapor which is needed for the induction 
of anaesthesia, and even with the use of closely applied masks it is not always 
possible to produce surgical anaesthesia by administering ether according to the 
drop method. Consequently, formerly ether was usually poured into the so-called 
half-closed masks, which were covered with impermeable material. 

Surgical experience has shown that these methods permit of anes- 
thetization with a satisfactory degree of safety, but they possess the 
drawback that the rapidity with which the drops should follow each 
other from moment to moment is entirely dependent upon a subjective 
estimate by the anaesthetist, and that it is impossible under such 
conditions to estimate accurately how much of the anaesthetic actually 
gets into the air inspired under the momentary conditions. Many 
attempts have therefore been made to construct apparatus which with 
greater certainty may be adjusted for certain concentrations. 

Anesthetizing Apparatus. — The first attempts to conduct anaesthesia in 
man with such measured mixtures were made by Paul Bert? Dreser 3 and Gep- 
pert, h'ionku, 1 , 2 Kcrmish, and many others have constructed various apparatus 
by the use of which the uncertainties and accidents of anaesthesia should be 
eliminated. These exact apparatus are, however, too complicated for general 
DBe, and liave therefore not been widely adopted. The I'oth-Drfigrr apparatus 
is one of the most widely used, and in it the anaesthetic is administered diluted 
Hrith oxygen. An absolute guarantee of the concentration of the anaesthetic in 
the respired air can bo furnished only by such apparatus as lead an already 
measured mixture directly into the air-passages but not through a more or less 
closely applied mask. Such apparatus are used in animal experiments (Kro- 
wfLi ■;•, Ratimoff, Vushnu) but the same principle may be utilized for man. 

Dependence of Absorption op the Type of Respiration. — If the 
anaesthetic be dropped on the mask or administered by means of 
apparatus through a mask which is not closely applied, the amount 
Which is actually respired is markedly influenced by the rale and final- 
ity of the respirations. With each inspiration air from the outside 
rushes under and through the mask, and consequently rapid and deep 



76 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

breathing on the part of the patient causes a dilution of the vapor 
under the mask, while the expirations force out a large portion of the 
anaesthetic which may be present in the mask, and thus, with active 
respiration, only a small portion of the anaesthetic used actually reaches 
the lungs. On the other hand, depression of the respiration necessarily 
to a high degree favors the accumulation of the anaesthetic inside the 
mask, and consequently, when for a considerable period the respira- 
tion is feeble, the air in the mask contains higher percentages of the 
anaesthetic. 

Individual Susceptibility or Idiosyncrasy. — Consequently a 
painstaking observation of the respiration is essential, no matter what 
method is used in the anaesthetization, and, at the same time, all 
the other symptoms must be closely watched, for even in animals the 
susceptibility of different individuals of the same species to anaes- 
thetics varies, and in man the susceptibility is subject to wide varia- 
tions, just as is the case with alcohol. Consequently, as expressed 
by v. Mikulicz, 1 every ancesthetization is a new experiment that must 
he continually controlled according to the reaction of the organism. 

Estimated by the average consumption of chloroform in the unit 
of time, women are generally more readily narcotized than men, and 
the resistance is greatest in middle life. It is well known with what 
difficulty chronic alcoholics are anaesthetized. 

Comparative Mortality. — If the effects of chloroform be compared 
with those of ether, the facts already mentioned are alone sufficient 
to show that, when the permissible concentration is exceeded, the 
direct danger to life is very much greater in chloroform narcosis than 
in ether narcosis. The statistics of the Deutsche Gesellschaft fur 
Chirurgie, 1903, place the mortality at one death in 3000 for chloro- 
form, and only one in 14,600 for ether.* 

Moreover, chloroform narcoses of rather long duration, even when 
carefully conducted, are accompanied by other dangers to the organ- 
ism (p. 74) , which cannot be avoided and which occur very rarely when 
ether is used. The hypersecretion which may cause serious after- 
effects when ether is used may, on the other hand, be avoided by the 
previous administration of atropine or scopolamine. Finally, the 
toxic action of chloroform on the heart forbids its use in patients with 
circulatory disease. 

That, in spite of all this, chloroform is used so much is explained 
by the fact that complete anaesthesia is much more easily obtained with 
chloroform than with ether. For operations lasting but a short time 
the analgesia alone is sufficient, which is already present in the stage 
of excitement produced by ether, the so-called half-narcosis (Sudeck, 
Mikulicz 2 ). 

* [Recent American statistics give the mortality as one in 2048 for chloro- 
form and one in 5623 for ether. (Gwathmev, J. of A.M.A., 1912, vol. lix, 
p. 1845).— Tr.] 









CHLOROFORM AND ETHER 77 

BIBLIOGRAPHY 

Ambrosius, Virchow's Arch., vol. 138. 

Aubeau, M. : Coinpt. rend, de la Soc. de Biol., 1884, June 20. 
Bandler: Grenzgebiete d. Med. u. Chir., 1896, vol. 1. 
Bernstein, I.: Moleschotfs Untersuch., vol. 10, p. 280. 
x Bert: Compt. rend, de l'acad. des sciences, 1885, p. 1528. 

2 Bert: Compt. rend, de la Soc. de Biol., 1884, Jan. 5. 

3 Bert: Journal de Pharm. et de Ckini., series 5, vol. 8. 

Bethe: Allgem. Physiol, des Xervensystems, Leipzig, 1903, p. 389. 
Blauel: Verhandl. des Chirurgenkongr., 1901, vol. 1, p. 132. 
Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 158. 
CuBhny: Zeitschr. f. Biologie, 1891, vol. 28. 
Diebafla: Arch. f. exp. Path. u. Pharm., 1894, vol. 34, p. 137. 
'Dreser: Beitr. z. klin. Chir., 1893, vol. 10. 

2 Dreser: Sitzungsber. d. Xiederrhein. Ges. f. Heilk. in Bonn, 1894. 
3 Dreser: Arch. f. exp. Path. u. Pharm., 1896, vol. 37. 

Dutrochet, Leclerc, et P. Bert: cited from Dastre, Les Anesthetiques, Paris, 1890. 
Elfving: Finsk. Velensk. Socis. Forh., 1886, cited from Richter, loo. cit. 
Embley: Biochem. Journal, 1910, vol. 5, p. 19. 
Ewald: Berl. klin. Woch., 1S75, No. 11. 
Frankel: Vircbow's Arch., vol. 127 
Gaskdi and Shore: British Medical Journal, 1893. 
Geppert: Deut. med. Woch., 1899. 

Gerlinger: Arch. f. exp. Path. u. Pharm., vol. 47, 1902, p. 438. 
Grossmann: Deut. med. Woch., 1895. 
Harcourt: Brit. med. Jour., 1905. 
Hitzig: Arch. f. Anat. u. Physiol., etc., 1873, p. 402. 
HSlscher: Langenbeck's Arch., 1898, vol. 57. 
Jenop: Lancet, 1874. 

Kast u. Mester: Zeitschr. f. klin. Med., vol. 18. 
Kegel: Dissertation Gottingen, 1905. 
Mvionka: Arch. f. klin. Chir., 1895, vol. 50. 
■Kionka: Arch. f. klin. Chir., 1899, vol. 58. 
Klipstein: Zeitscbr. f. klin. Med., vol. 34. 
' Knoll: Sitzungsber. d. Wiener Akad., 1876, vol. 74. 
-Knoll: Sitzungsber. d. Wiener Akad., 1878, vol. 78. 
Krapelin: Ueber die Beeinflussung psycb. Vorgiinge, etc., 1892. 
Kratschner: Sitzungsber. d. Wiener Akad. d. Wissensch., 1870, vol. 26. 
Kronecker u. Elatimoff: Dubois Arcb., 1884. 
Ku --maul: Virchow's Arch. f. patb. Anat., 1858, vol. 13. 
Loeb: Arch. f. exp. Path. u. Pliarm., 1904, vol. 51, with literature. 
1 >rikuli<-x. : Deut. Klinik., vol. 8. 
•Mikulicz: Berl. klin. Wocb., 1894. 
Neubauer: Milnchn. med. Woch., 1900, No. 17. 
Niclonx. M.: J.cs Ancstliesiques grneraux, Paris, 1908. 

Nutlmagcl u. Rossbacb: Ilandb. d. Arzneimittellebre, 6th Edition, p. 412, Ber- 
lin. 1887. 
' Nothnagel: Berl. klin. Woch., L866. 
Nussbaum: LJeber Chloroformwirkung, Breslau, 1884. 
Ostertag: Virchow's Arch., vol. 118. 

Pick, I'r.: Arch. f. exp. Patb. u. Pbarm., 1899, vol. 42, p. 399. 
flohls Anh. f. exp. Path. u. Pharm., L891, vol. 28. 
Ratimoff: l>u Bois' Arch. f. Physiol., L884, p. 576. 
Richter, O.: Med. Klin., 1907, No. L0. 
Rindskopf: Deut. med. Woch., 1893, No. 40. 
Rosemann: Pflflger's Arch.. 1901, vol. si;, p. 307, here literature. 
1 Rosenfeld: Arch. f. exp. Path. a. Pharm., 1896, vol. 37. 
'Rosenfeld: Studien Uber Organverfettungen, Arch. f. v\\>. Path. u. Pharm., 

1906, vol. .">."». 
Rubow: Arch. f. exp. Path. u. Pharm., 1904, vol. 52. 
1 Bcheinesson : 1 kiss., I lorpat, 1 B68, 
'Bcheinesson: Archiv. d. Ilcilkunde, 1869, p. 172. 



78 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Schmey, P.: Inaug.-Diss., Berlin, 1885, p. 11. 

Selbacli: Arch. f. exp. Path. u. Pharm., 1894, vol. 34. 

Sherrington and Sowton: Br. Med. Journal, 1904. 

Snow: London Journal of Medicine, 18o2. 

Spenzer, I. G.: Arch. f. exp. Path. u. Pharm., 1894, vol. 33. 

Strassmann: Virchow's Arch., vol. 115. 

Sudeck: Deut, med. Wocli., 1901. 

Ungar: Vierteljahrschriit f. gerichtl. Med., vol. 47. 

Waller: Brain, 1896. 

Zeller: Zeitschr. f. physiol. Chemie, 1883, vol. 8. p. 70. 



COMBINED ANESTHESIA 

In order to avoid the chief disadvantages of ether, which are pre- 
sented by the slow or difficult induction of insensibility and the usually 
very pronounced stage of excitement, the anaesthesia is often started 
with chloroform and then continued with ether. The use of ethyl 
bromide (Koclier) for this purpose has been properly abandoned.* 
It has also been possible to augment the anaesthetic effects of ether by 
combining it with other narcotics. 

Soon after the introduction of general anaesthesia, on purely empiri- 
cal grounds it was found advantageous to make use of mixtures of 
ether and chloroform, often with the addition of alcohol, in prefer- 
ence to using either of these anaesthetics alone. Apparently anaes- 
thesia with such mixtures is less attended by the danger of depression 
of the heart and respiration than is pure chloroform anaesthesia. 

In such mixtures the alcohol plays hardly any other role than that 
of diluent (Filehne and Biter f eld), for it is only the diminution of 
the vapor tension of the anaesthetics, caused by the addition of the 
alcohol, which can be of any significance, for, in its presence, the 
evaporation of the actually efficient constituents of the mixture is 
retarded, and thus the danger of overdosage is lessened. 

With the combination of ether and chloroform, on the other hand, 
newer investigators of the reciprocal synergistic effect of the narcotics 
have raised the question whether the narcotic actions of ether and 
chloroform, when thus used, are simply superimposed on each other, 
or whether, as has also been assumed, they synergistically produce an 
increased effect. In the first case, half of the vapor concentration of 
ether necessary to produce anaesthesia and half of the similarly effective 
concentration of chloroform should be sufficient to produce anaesthesia, 
but should do no more than this. If, on the other hand, by their simul- 
taneous action a synergistic increase in their action results, perhaps 
on account of a greater absorption of chloroform by the nervous 
tissues (Fiihncr), the total effect should be greater than would be 
expected from the simple addition of their separate effects. 

* [In the United States the less dangerous ethyl chloride is widely used 
as a means of easily, safely, and pleasantly starting the anaesthesia, and where it 
has been used has met with much favor. — Tr.1 



MORPHINE-SCOPOLAMINE ANAESTHESIA 79 

Honigmann believes that he has been able, by experiments on animals, to 
show that this greater effect is produced, yet the average values obtained in his 
experiments do not indicate this, but only those obtained under special conditions. 
On the other hand, Madelung, by continuously administering exactly measured 
mixtures of ether and chloroform, was able to produce only that degree of 
anaesthesia which was to be expected as a result of a simple addition of the 
separate effects. In his experiments mixtures containing less than half the 
amount of chloroform necessary to produce anaesthesia failed to produce anaes- 
thesia when combined with a concentration of ether equal to one-half of the 
anaesthetizing concentration. His results agree with those obtained by Biirgi, 
who was also unable to obtain any synergistic strengthening of the action of 
the hypnotics of the alcohol group, chloral hydrate and urethan, whose action 
is in principle the same as that of chloroform and ether. The advantage ( ? Tk. ) 
of anaesthesia induced by such mixtures may consequently be attributed only to 
the fact that the dangerous actions of chloroform are exerted in the production 
of only one-half of the total narcotic effect. 

BIBLIOGRAPHY 

Biirgi: Deut. med. Woch., 1910, Xo. 1. 

Filehne u. Biberfeld: Zeitschr. f. exp. Path. u. Therap., 1906, vol. 3, p. 171. 

Fiihner: Berichte d. deut. Chem. Ges., 1909, vol. 42, p. 887. 

Fiihner: Deut. med. Woch., 1910, No. 2. 

Honigmann: Arch. f. klin. Chir., 1899, vol. 58. 

Kocher: Chirurg. Operationslehre, Jena, Fischer, 1902. 

Madelung: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 409. 

MORPHIXE-SCOPOLAMINE ANESTHESIA 
On the other hand, by combination with substances like morphine 
and scopolamine, which depress the central nervous system in a dif- 
ferent manner, it is possible to produce a distinct augmentation of the 
narcotic effects of the gaseous anaesthetics. A preliminary injection 
of 0.01 gm. of morphine with 0.5 mg. of scopolamine not only prevents 
that stage of excitement which ordinarily is so disturbing at the 
commencement of anaesthesia, but in addition it renders it possible to 
induce and maintain a satisfactory anaesthesia with distinctly lower 
concentrations of the anaesthetic in the air inspired. 

In experiments on animals it has been possible to confirm this clinical ex- 
perience in an exact fashion, Madelung, after previous injection of doses of 
morphine and scopolamine, which by themselves produce no narcotic effects, hav- 
ing been able to induce a deep narcosis with air containing only 2.5-3 volume 
per cent, of ether, although the controls which had not received such injections 
required 4.5 per cent, of the anaesthetic for the induction of equally deep anaes- 
thesia. Consequently, after the previous administration of these two drugs, 
human beings may be satisfactorily anaesthetized with minimal amounts of chloro- 
fonn, or, in case ether he used, they may he readily anesthetized by the safe 
drop method. Iii addition, scopolamine possesses the advantage, as has already 
been mentioned (p. 76), of inhibiting the secretion of saliva. 

A- stated by Schneiderlin, Korff, and many others, it is possible to produce 
with morphine and scopolamine alone a condition of analgesia and clouded 
consciousness (twilighl Bleep) in which even relatively major operations may be 
I'.iinhvssly performed. It was such observations which first directed attention 
to the striking intensification of the effects of morphine which is caused by 
Scopolamine and which may he readily demonstrated in experiments on animals 
i /v.' hmann ) . 

Some time ago morphine-scopobmiinc narcosis was actually recom- 
mended as a substitute for the general anaesthesia induced by inhala- 



80 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

tion ; but further clinical experience, supported by the results of 
experiments on animals, has demonstrated that those doses, which ivith- 
out the aid of one of the gaseous anesthetics cause a narcosis of 
sufficient depth, carry tvith them greater dangers than any of the other 
various methods of producing anaesthesia (Kochmann) . 

In principle, any narcosis produced by injecting a drug must repre- 
sent a step backward when contrasted with anaesthesia produced by 
inhalation, for, when non-volatile narcotics are administered, one loses 
the greatest of advantages, — namely, the ability to interrupt the 
anaesthesia at the appearance of dangerous symptoms, and to secure 
the elimination of the drug in the most rapid manner possible by 
elimination through the lungs. Doses of morphine and scopolamine 
which, when given together, prepare the patient satisfactorily for 
an anesthesia by inhalation are without danger. At the present time 
they are also often employed to produce a certain degree of cloudiness 
of the consciousness and loss of memory during parturition {Gauss, 
Kronig, Mansfeld, Bjorkenheim). When used for this latter indi- 
cation, the morphine should be cautiously administered, in order to 
avoid the danger to the respiration of the new-born child, which has 
already been mentioned on page 35. While 0.3-0.6 to 1.0 mg. of scopo- 
lamine, administered in several injections, may be safely given, it is 
not well to increase the dose of morphine beyond 0.01 gm. in labor cases. 

BIBLIOGRAPHY 

Bjorkenheim: Ergehnisse d. Geburtshilfe u. Gynakologie, 1911, vol. 2, p. 1. 

Gauss: Archiv f. Gynakologie, vol. 7S. 

Kochmann: Arch. int. de Pharmacodynamic, 1903, vol. 12. 

Kochmann: Miinchn. med. Woch., 1905. 

Korff: Munch, med. Woch., 1901, No. 29. 

Kronig: Deut. med. Woch., 1908, No. 23. 

Mansfeld: Wien. klin. Woch., No. 1. 

Madelung: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 409. 

Schneiderlin; Aerztliche Mitteil. aus & f. Baden, May, 1900. 

NITROUS OXIDE ANAESTHESIA 

The great majority of accidents during chloroform and ether nar- 
coses occur during minor operations, for which one attempts to induce 
an anesthesia of short duration too rapidly and without sufficient 
assistance. The introduction of nitrous oxide, as a means of rapidly 
producing a narcosis of short duration, was consequently an important 
step of progress, although to-day local anesthesia has almost entirely 
driven this method out of the field for minor surgical procedures. 

Nitrous oxide, N 2 0, whose powers of causing intoxication are responsible 
for the discovery of inhalation anaesthesia, was actually introduced into practice 
only at a much later date, the sixth decade of the last century. 

This substance is a colorless gas with a weak, sweetish odor, heavier than 
air, and rather soluble in water. It is prepared by heating ammonium nitrate, 
NH 4 N0 3 , which is readily decomposed into NX) + 2H 2 0. It may be obtained com- 
mercially, condensed under high pressure in iron cylinders. 



NITROUS OXIDE 81 

Like hydrogen or nitrogen, nitrous oxide when inhaled produces 
no irritating effects. Although able, outside of the body, to support 
combustion even better than air, in the body it is unable to maintain 
the respiratory changes of the tissues. Consequently, nitrous oxide 
may be administered for only a very short time if it be inhaled pure 
and free from oxygen. 

The possibility of utilizing in practice the inhalation of pure 
nitrous oxide depends upon the fact that, during the very rapid 
absorption of this gas by the blood, narcosis is produced before suffo- 
cation. That nitrous oxide narcosis is not due to this suffocation alone 
is quite evident from the fact that the typical convulsions due to 
asphyxia do not occur in warm-blooded animals when it is administered 
alone, although with complete withholding of oxygen without the 
action of any narcotic such convulsions would necessarily occur at 
the end of the first minute. 

If a human being be caused to inhale undiluted nitrous oxide with 
complete exclusion of the air, and the expired air or gases be permitted 
to escape through a valve, a condition resembling intoxication rapidly 
develops, and after about one minute the consciousness disappears and 
anaesthesia and relaxation of the muscles appear at the same time with 
rather pronounced cyanosis. If now the patient be allowed to breathe 
air again, the anaesthesia lasts about half a minute longer, and at the 
end of another half minute recovery occurs rapidly (Binz). 

It is thus evident that, when pure nitrous oxide unmixed with air 
is breathed, unconsciousness results at a much less dangerous stage of 
asphyxia than is the case with pure suffocation (Zuntz and Goldstein) . 
If animals continue to breathe nitrous oxide after the dyspnoea, which 
at the start was inspiratory in character, has altered its type to the 
expiratory one, the convulsions which ordinarily occur during suffo- 
cation do not occur, and the animals die as a result of asphyxia, the 
heart continuing to beat for a considerable period after the respiration 
has become paralyzed. 

The narcotic action of nitrous oxide may be especially well demonstrated 
on the frog, which is not affected by tbe lack of oxygen in the atmosphere except 
after many hours. Although these animals, when kept in an atmosphere of 
hydrogen for hours at a time, remain reflexly excitable and capable of motion, 
when placed in pure nitrous oxide they quickly become motionless and no longer 
react to sensory irritation such as that produced by the application of acetic 
acid to the skin. If now the frog be again brought into the air, after a few 
minutes reflex excitability and the motor function return. The very interesting 
experiments of Paul Bert, to which we will soon return again, have clearly shown 
that nitrous oxide produces a narcotic effect in man even when all elements of 
suffocation or asphyxia are excluded, provided only that the blood be saturated 
with a sufficient quantity of this gaa. 

If nitrous oxide, diluted with enough oxygen to prevent suffo- 
cation, be inhaled, symptoms are observed which L. Hermann thus 
describes, from experiments made upon himself: "One perceives the 
6 



82 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

distinctly sweetish taste of the gas, and soon buzzing and drumming 
in the ears are felt, visual impressions become very indistinct, and 
there is a feeling of increased warmth and of extraordinary lightness 
of the limbs, this latter probably being due to the loss of the muscle 
sense. ' ' The muscular movements become very uncertain ; there is some 
depression of the susceptibility to painful impressions and to a less 
degree to touch. ' ' The flow of ideas is abnormally rapid, and usually 
there is loud laughing. Consciousness is never completely abolished, 
and complete anaesthesia also does not occur. If the inhalation of the 
gas is then interrupted, the normal condition is very quickly 
re-established. ' ' 

A complete narcosis does not result from the breathing of nitrous 
oxide diluted with oxygen, for the reason that the partial pressure of 
nitrous oxide in a mixture containing 21 volumes per cent, of oxygen 
is not sufficient to cause the blood to absorb a sufficient amount of 
this relatively feeble narcotic. For the production of a complete 
anaesthesia the partial pressure of the nitrous oxide must reach 
760 mm. of Hg, one atmospheric pressure. In order to attain this 
it is necessary either to have the nitrous oxide administered undiluted, 
— that is to say, under a pressure equivalent to one atmosphere, — and 
under such conditions asphyxia will quickly follow on the anaesthesia, 
or, as was first done by Paul Bert, 20 per cent, of oxygen is intro- 
duced under pressure into nitrous oxide without increasing its volume, 
and this mixture is administered under a pressure of one and one- 
fifth atmospheres. This author was able to show that in this fashion it 
is possible without danger to produce and to maintain a deep narcosis. 

However, the actual handling of such narcotic mixtures under 
pressure is too complicated for every-day use, and consequently nitrous 
oxide is employed only for narcoses lasting but a very short time, in 
which case the pure gas is administered, or for light, incomplete anaes- 
thesia, in which nitrous oxide with oxygen is administered. Pure 
nitrous oxide may be allowed to flow from the cylinder into a rubber 
bladder from which it is inhaled through a mouth-piece, the expired 
air escaping through a valve. A simple readjustment of the apparatus 
permits the administration of air at the end of the first minute. For 
the incomplete anaesthesias one administers a mixture of 80 per cent, 
nitrous oxide and 20 per cent, oxygen, the so-called laughing gas, 
which, under ordinary atmospheric pressure, produces only a condition 
resembling intoxication, which is entirely free from danger and in 
which there is a simple clouding of the consciousness with analgesia. 

Nitrous oxide mixed with enough oxygen to support the respiration 
(20-15 per cent.) does not produce complete anaesthesia, because under 
such a partial tension of four-fifths of an atmosphere the nitrous 
oxide does not become sufficiently concentrated in the blood. However, 
in combination with doses of morphine and scopolamine, which are 



ETHYL BROMIDE 83 

in themselves entirely safe and which alone produce no narcotic 
effects, the effect of such mixtures of nitrous oxide and oxygen is 
sufficient to produce a satisfactory anaesthesia. In this way laughing 
gas may be utilized for anaesthesias lasting for considerable periods 
and is adapted to major operations (Neu). The chief advantages of 
such anaesthesias are that nitrous oxide produces no irritating effects 
on the respiratory organs and but slight side actions, and that recov- 
ery occurs with unusual rapidity. After cessation of its administration 
the nitrous oxide content of the blood very rapidly falls below the 
minimal amount which produces any effect. Animals may become 
entirely normal within 1-2 minutes after the interruption of the deep 
anaesthesia produced by this method. 

BIBLIOGRAPHY 

Bert, P.: Gazette med. de Paris, 1878 and 1879. 

Binz: Vorles, p. 37. 

Hermann, L. : Lehrb. d. exp. Toxikol., Berlin, 1874, p. 244. 

Xeu: Munch, med. Woch., 1910, No. 36. 

Zuntz u. Goldstein: Prliiger's Arch., vol. 17. 

Ethyl bromide, C 2 H 5 Br, is a colorless volatile fluid, boiling at 
38-39° C. It is readily decomposed under the influence of light 
and air, and should consequently be kept in brown bottles as nearly 
full as possible. It may now be obtained in very pure form, but prep- 
arations colored brown are not to be used. 

Ethyl bromide anaesthesia has some advantages similar to those 
of nitrous oxide anaesthesia, for it is much more readily induced and 
conducted. "When a considerable amount — say 5.0-10.0 gm. — of ethyl 
bromide is poured into the half -closed impermeable mask, the anaes- 
thesia develops extremely rapidly after 10-20 inhalations. If within 
one and one-half minutes the desired effect has not been obtained, 
its administration is not to be continued, for this would be attended 
with considerable danger. When the drop method is employed for 
the administration of ethyl bromide, the anaesthesia also develops 
comparatively rapidly, and the stage of excitement is ordinarily com- 
paratively short and the recovery from the narcosis is rapid. After 
recovery, a taste of garlic in the mouth and a similar odor on the 
breath, which often lasts for 24 hours or longer, is very disagreeable 
and disturbing. Vomiting occurs much less frequently than after 
chloroform. 

However, ethyl bromide should not be employed for deep or com- 
plete anaesthesia, because the respiratory function is markedly affected 
by it, cessation of respiration occurring almost simultaneously with 
the abolition of the reflexes. It is also unsuitable for operations lasting 
for a considerable period, because the anaesthesia is likely to run along 
somewhat irregularly, and especially because, as a result of its long- 



84 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

continued action in the body, secondary disturbances and injury to 
the internal organs occur to an even greater extent than after chloro- 
form and may produce serious late effects. Dreser has demonstrated 
these late effects in animals. 

BIBLIOGRAPHY 

Dreser: Arcli. f. exp. Path. u. Pharm., 1895, vol. 3G. 

HYPNOTICS OF THE ALCOHOL GROUP 

Another group of substances, which in their basic actions follow 
the type of the alcohol group, are used as hypnotics. As such we 
may use those members of the alcohol group whose behavior in respect 
to their absorption makes it possible to confine their action to that 
of the very early stage, and to maintain this first stage for hours. 
However, a regular and not too rapid absorption and a gradual elimina- 
tion are not in themselves sufficient to make all the substances of 
the alcohol group possessing these qualities utilizable as hypnotics, 
for with many a primary motor excitation produces disturbing effects, 
and in others harmful side actions on the respiration and circulation 
or on the metabolism are too readily caused when the therapeutic 
dose is exceeded. 

The pharmacological action of the hypnotics is in all essential 
points typical of that of the alcohol and chloroform group. With 
such an hypnotic as chloral hydrate, it is possible to observe and to 
distinguish all the stages of narcosis when it is administered to higher 
laboratory animals, such as rabbits. At the start the first thing 
noted is that the animals move less frequently than usual and react 
less to psychic impressions. In addition to this action on the cerebrum, 
even in the first stage, the centres in the midbrain, cerebellum, and 
medulla, which control motor coordination, are also affected. In the 
second stage the depression of the cerebrum is more pronounced and 
the centres of coordination are still more affected, so that the animal 
is no longer able to rise up but remains lying on the side. In this 
stage the corneal reflex is diminished, but the respiration is only 
slightly slowed, while the weakened resistance shown by the animal, 
when the attempt is made to extend its legs, indicates that the spinal 
cord, too, is involved in the narcosis. In contrast to the effect of mor- 
phine, the animal in this stage reacts more actively to painful stimuli 
than does a normal one, kicking actively when pinched and raising itself 
up for a short time. These pain reflexes become feeble only gradually, 
and disappear only when the corneal reflex is almost completely abol- 
ished and when pulling on the extremities no longer excites resistance 
(K'nppcn). Finally, in the last stage all the reflexes, including the 
corneal, are completely abolished, the breathing becomes slower, and 
death finally results from paralysis of the respiration. 



THE HYDROCARBON HYPNOTICS 85 

Side Actions. — "With, different hypnotics the Mood-pressure behaves 
differently in the different stages, and the respiration is also affected 
in different degrees. After choral hydrate, for example, as a result 
of vasomotor depression, the blood-pressure falls markedly in the 
second stage at a time when the corneal reflex is still present. The 
heart-beat is also slowed early and the respiration is distinctly dimin- 
ished in frequency. With other hypnotics, on the other hand, dis- 
turbances of the circulatory and respiratory centres and depression 
of the heart develop only in the last stages, just a short time before 
the abolition of the corneal and all other reflexes. 

From the above description it may be seen that the complete 
narcotic action affects the centres in the different portions of the 
central nervous system, but that, following the general type of the 
action of the alcohol and chloroform group, the depression first affects 
the cerebrum and then the spinal cord, while the vital centres in the 
medulla are the last to be markedly affected. 

It is only in the first stage of the action of the hypnotics that a 
condition develops which corresponds to normal sleep. Under their 
influence dogs fall asleep, assuming their normal sleeping posture, 
but they may be readily awakened at any time, the muscle tone relaxing 
as in normal sleep while the breathing is no more slowed than in normal 
sleep. The only difference appears to be that on waking from such 
artificial sleep the disturbance of coordination is more marked than on 
waking from natural sleep, this effect persisting longer than the others 
after waking. It is only these first grades of their pharmacological 
actions which are utilized when these substances are employed as 
hypnotics, the essential factor being the depression of the excitability 
of certain of the cerebral sensory functions. The hypnotics heighten 
the threshold for the conscious perception of sensory impressions, this 
being just what is necessary for 

Falling asleep. — Unfortunately, our knowledge of the physiologi- 
cal causation of falling asleep is not satisfactory. Probably the accu- 
mulation of fatigue substances, formed during the activity of the ner- 
vous system, gradually produces the tendency to fall asleep. When 
this has occurred, it is under normal conditions sufficient to cause an 
individual to fall asleep, if the stimuli from the outer world, which are 
constantly reaching the brain through the organs of sense, are weak- 
ened as much as possible. When endeavoring to fall asleep, Ave darken 
the room and shut oul noises, secure an equable warmth, and free 
ourselves from uncomfortable elothing, — in short, we purposely cut 
out all the stronger stimuli which act on the organs of sense, and, 
as a rule, this is sufficient, for, in the quiet state which precedes 
the dropping asleep, feebler stimuli no Longer reach our consciousness. 

Causes of Insomnia. — The essential factor of the so-called essential 
sleeplessness is an over-excitability of ihe cerebral corlex, as a conse- 
quence of which, normal stimuli, which ordinarily are subliminal, in 



86 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

spite of the quiet, still reach the consciousness when the attempt is 
made to go to sleep. Sleeplessness may, however, even with a normal 
excitability of the cerebral cortex, be due to too powerful stimuli, such 
as psychical activity, excitement produced by feelings of discomfort, 
sorrow, etc., which may prevent sleep, or external pathological stimuli, 
like pain, dyspnoea, cough, etc., may produce the same effects. In 
such cases, in which severe bodily symptoms interfere with the falling 
asleep, the sleeplessness is best relieved by removal of these pathological 
irritations, if this can be done. For example, digitalis will be the 
best hypnotic if disturbances of the heart be the cause of the sleep- 
lessness. If, however, it is not possible to remove the cause of the 
pathological stimuli, the prevention of the perception of these stimuli 
will permit sleep. 

In the case of pain, cough, or dyspnoea, this is best accomplished 
by that specific pain reliever, morphine. In essential sleeplessness, not 
due to abnormal stimuli but primarily the result of pathological excita- 
bility of the cerebral cortex, the hypnotics of the alcohol group are 
far more useful than the morphine group. On the other hand, in the 
presence of severe pain, they are effective only in doses large enough 
to cause a general narcosis of numerous cerebral centres. Such doses 
may be employed in the presence of extreme degrees of marked 
cerebral excitement, for example in maniacal patients, and may pro- 
duce the necessary quieting effect even on the cerebral motor centres. 
The proof that small doses of hypnotics produce no other effect than 
to prevent sensory stimuli from reaching the consciousness has been 
best supplied by Erapelin's experiments in which he tested the effect 
of various waking stimuli in light sleep and in sleep produced by 
hypnotics. 

INFLUENCE OF HYPNOTICS ON THE DEPTH OF SLEEP 

When the brain is over-exeitable, one cannot fall asleep, because even the 
slightest stimuli wake one up. If the drowsy condition of falling asleep has 
once passed over into a condition of unconscious sleep, under normal conditions 
the sleep rapidly becomes deeper and, although individuals show marked differ- 
ences in this respect, the maximum soundness of sleep is usually attained inside 
of the first hour. Systematic experiments, in which it was determined what 
intensity of noise was sufficient to wake the subject up after he had been asleep 
for a definite period of time, have shown how great are the differences in the 
soundness with which different persons sleep. The height of the waking 
threshold during a certain period of sleep may be used as the measure of the 
soundness of sleep. If now these waking threshold values are expressed in 
curves, sleep curves for the different periods of the experiment may be obtained 
which indicate graphically the more or less rapid rise to the maximum soundness 
of sleep and the gradual fall up to the time of awaking {Kohlschiitter) . 

With good normal sleep the summits of the curves are higher and are more 
rapidly attained than with poor sleep, in which the curve expresses an insuffi- 
cient soundness of sleep during the first hours and then runs along at about the 
same moderate height, instead of falling in the morning as an expression of the 
awakening in a refreshed condition. Under the influence of an hypnotic, for 
example, of paraldehyde, a light and insufficient sleep is induced which approaches 
the type of normal sleep. 



MODE OF ACTION OF HYPNOTICS 



87 



In Fig. 7 the curves obtained by Michelson by observations, under as con- 
stant conditions as possible, on afternoon sleep lasting several hours, with and 
without paraldehyde, are given as evidence of this. The two curves, Ila and lib, 
which were obtained under the influence of paraldehyde, in comparison with 
curve I, the curve of normal light afternoon sleep, show a much more pronounced 
soundness of sleep, as they rise much more sharply and thus resemble the 
type of normal sleep during the night. 



psychical reactions in 



The results of investigations of simple 
individuals, who had taken some hypnotic, 
are in complete agreement with this demon- 
stration that these hypnotics diminish the 
efficiency of waking stimuli, for Krapelin 
and his collaborators have shown that an 
impairment in the perception of external 
stimuli is a characteristic effect of the hyp- 
notics (paraldehyde, chloral hydrate, trional), 
which is also produced by alcohol. Small 
doses of morphine do not produce this effect 
on the function of perception, and conse- 
quently they are not to be considered as 
true hypnotics. 

In addition, the different hypnotics, 
although in very varying degrees, also ren- 
der more difficult the initiation of motor 
nervous impulses. While paraldehyde and 
particularly alcohol impair motor functions 
only after large doses, and in smaller doses 
act as motor stimulants, chloral hydrate 
and trional, from the very start, in addi- 
tion to impairing the perception of sensory 
impressions, -show a tendency to produce a 
quieting of the motor functions (Hanel). 
Consequently these latter have the power of 
producing a pure hypnotic effect without 
any disturbing symptoms of intoxication, 
while alcohol may only in a limited sense be 
described as a hypnotic, for the primary motor 
excitement, caused by it in many individuals, . 
produces waking stimuli and thus prevents the falling asleep. 



|J> 

ji /\ 

ij / 
i 


\ 

\ 

\ 

\ 

\ 

\ 

l 1 




.Ma 
I 






O ) 




? 


? 4 


J 



Fig. 7. — I, curvo indicating 
depth of sleep in an afternoon 
nap lasting several hours; Ila, 
lib, curves obtained under 
paraldehyde, conditions other- 
wise similar. 



IMPORTANCE OF THE RATE AT WHICH HYPNOTICS ARE ABSORBED AND ELIMINATED 

This cutting out of external stimuli by the hypnotics produces the essen- 
tial conditions for the development of sleep. As in neurasthenics the inability 
to fall asleep, except late and with great difficulty, is often the chief disturbing 
symptom, in these cases the most important desideratum is to deepen the sleep 
at the very start. Consequently, the readily absorbable hypnotics, chloral hydrate, 
paraldehyde, and the like, are the best means of helping such patients to fall 
asleep. "With other forms of disturbed sleep, for example, in the typical disturb- 
ance of sleep commonly met with in the aged, the patient falls asleep easily 



88 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

enough, but soon after wakes up again, and then cannot sleep again. With 
insomnia of this type hypnotics possessing a more lasting action are indicated, 
for example, trional, which Hanel was able to demonstrate caused a diminution 
in the power of perception which persisted into the following day. 

In general it is essential for hypnotics that their action be rapidly 
produced and persist for a sufficient period. Both of these desiderata 
will be best accomplished by substances which are soluble in water, 
which distribute themselves equally in the stomach contents, and 
which, after gradual passage into the intestine, are gradually absorbed. 
At the same time hypnotics must not be excreted or destroyed too 
rapidly, while, on the other hand, a too slow excretion or destruction 
is also undesirable, because under these conditions the effects would 
persist on the following day, as has often been observed after the 
administration of sulphonal and trional, as also after veronal. 

Freedom from Harmful Side Actions. — Above all, however, all 
hypnotics should, in therapeutic doses, produce no dangerous side 
effects on the circulation, respiration, or metabolism, and also should 
not disturb the stomach. With the augmentation or frequent repetition 
of the dose, naturally all hypnotics are dangerous. In the presence 
of an especial individual susceptibility or of pathological conditions, — 
e.g., cardiac or pulmonary disease, — these side actions, especially in the 
case of the more powerful hypnotics, may be produced even by the 
doses which are necessary in order to produce sleep. This is the case, 
however, to an even greater degree with those larger doses of hypnotics 
which are employed in conditions of psychic excitation, with the object 
of exerting a sedative effect on the cerebral motor centres, or which 
are used as antidotes in poisoning by convulsant poisons, or in tetanus, 
etc., in order to depress the excitability of the spinal cord. 

BIBLIOGRAPHY 

Hanel: Krapelin's psychophysiche Arbeiten, 1897, vol. 2, No. 2. 
Kohlschiitter: Ztschr. f. rat. Med., 1863, vol. 17. 
Koppen: Arch. f. exp. Path. u. Pharm., 1892, vol. 29, p. 327. 
Michelson: Krapelin's psychophysiche Arbeiten u. Diss. Dorpat, 1891. 
Monninghoff u. Piespergen: Ztschr. f. Biol., 1883, vol. 19. 

CHLORAL HYDRATE 
Chloral hydrate is the member of this group which has been longest 
in use. It occurs in the form of dry transparent crystals with an 
irritating odor and a mildly bitter and pungent taste. It is very 
soluble in water, alcohol, and ether, and is quite hygroscopic. Con- 
centrated solutions strongly irritate the mucous membranes, and 
consequently this drug should always be administered sufficiently 
diluted and never in solid form, otherwise its irritating action on 
the stomach mucous membrane may cause discomfort. 

Chloral hydrate is formed of chloral and one molecule of water. Chloral 
itself, CClg.COH, or trichloracetaldehyde, the aldehyde of trichloracetic acid, is a 
colorless corrosive fluid. It was first prepared by Liebig, in 1832, by the action 



CHLORAL HYDRATE 89 

of chlorine on ethyl alcohol, the method still used in its manufacture. Chloral 
unites with water with the development of heat to form chloral hydrate, the 
equation of the reaction being CC1 3 .C0H + H,0 = CC1 3 .CH ( OH ) ,. According to 
Victor Meyer and Caro, this water is not combined as water of crystallization, 
but is a dihydroxyl combination, for, in contradistinction to chloral, it no longer 
contains an aldehyde radical. 

The reaction between chloral hydrate and aqueous solutions of 
the alkalies is of particular interest. Chloral is decomposed by the 
alkalies, with the formation of chloroform and formic acid, a reaction 
which takes place at ordinary temperatures and still more readily 
under the influence of heat, according to the following formula: 

CCI3.COH + KOH = CHCI3 + HCOOK. 

It is this decomposition of chloral with the formation of chloro- 
form which in 1869 suggested to Liebreich the hypothesis that chloral 
hydrate was gradually broken up by the alkaline reacting blood, with 
the formation of chloroform, and that thus a continuous chloroform 
effect would be exerted in the body. While this hypothesis has been 
shown to be incorrect, it was responsible for the introduction into 
therapeutics of the first synthetically formed hypnotic. 

As a matter of fact, chloral hydrate is not decomposed in the body, 
but produces its effects as unchanged chloral. This is shown by the 
fact that almost all of it is excreted undecomposed but in combination 
with various substances. Furthermore, the carbonate alkalinity of 
the blood is not sufficient to decompose chloral hydrate at the body 
temperature in the manner in which this decomposition occurs in the 
test-tube. 

Moreover, in case such a decomposition of chloral hydrate took 
place in the body to any recognizable extent, chloroform would neces- 
sarily be present in the expired air, but, according to Hammarsten, 
Hermann, and Tomascevicz, even the most delicate reagents fail to 
indicate its presence here. Chloroform is also not present in the blood 
of chloralized animals, although chloral hydrate may be demonstrated 
therein in all periods of the narcosis (Archangelsky). 

FATE IN THE BODY 

Chloral hydrate, as already mentioned, is almost completely excreted in the 
urine, chiefly as trichlorethylglycuronic acid or urochloralic acid, and only in 
very small amounts as unchanged chloral hydrate. A very small portion is 
retained in the body for a considerable time and is gradually decomposed, 
with a resulting increase of the chlorides in the urine, which persists for some 
time 1 Liebreich, lsiiii). 

During il- transformation into urochloralic acid, which is pharmacologically 
inert, chloral, which is a halogen substituted aldehyde, is lirst reduced to an 

alcohol before combining with glycuronic acid. The combination of chloral with 

glycuronic acid is thus seen to be a process similar to that by which numerous 
substances of the aliphatic series, and particularly aromatic substances, are dis- 
toxicated {Musculus ». Mering, h'iilz). 

This combination of drugs with glycuronic acid is of some importance to 
the practising physician, inasmuch as some of these combinations, for example 
urochloralic acid, reduce cupric oxide in alkaline solutions. Urine containing 



90 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

such combined glycuronic acid may consequently give a reaction which might 
lead to an erroneous conclusion that they contain sugar. Glycuronic acid is, 
however, not fermented by yeast and in combination polarizes light to the left. 

Therapeutic Employment. — As a rule, in doses of 1.0 gm. for an 
adult, chloral hydrate produces sleep, and in doses of 2.0-3.0 gm. 
causes profound sleep. As a result of its ready solubility and absorba- 
bility, sleep usually follows very promptly on its administration, lasts 
about 8 hours, and is usually not followed by any after-effects. In 
some individuals exanthematous eruptions are caused by chloral, while 
in others the local irritating effect in the stomach causes gastric dis- 
turbance. Idiosyncrasies toward it may also be met with, as a result 
of which it fails of producing hypnotic effects and, in place of so doing, 
even causes considerable excitation. Consequently, the first dose of 
this drug should not exceed 1.0 gm. (Stint zing) . 

Much larger doses, exceeding even the ordinary maximum dose of 
3.0 gm., may be necessary to produce the desired sedative effects 
in conditions of mental excitement, in delirium tremens, or in the 
convulsions of eclampsia, tetanus, or strychnine poisoning. With such 
doses, however, the dangerous actions of this drug may manifest 
themselves to a very appreciable degree. 

These harmful actions of chloral hydrate consist chiefly in 
harmful effects on the heart and on the vessels. Inasmuch as its 
actions, in general terms, resemble a protracted mild chloroform action, 
the vasomotor centres and the heart are depressed relatively early, 
just as is the case with chloroform. In patients with fatty hearts, 
myocardial degeneration, arteriosclerosis, etc., these dangerous actions 
may manifest themselves even after ordinary hypnotic doses, and 
after large doses sudden heart death may occur in such patients. Like 
chloroform, chloral hydrate, even in therapeutic dosage, may cause 
a fall in the blood-pressure as a result of a commencing vasomotor 
depression, and the pulse may become soft with increased amplitude. 
The differences between the therapeutically effective concentrations in 
the blood and the concentrations which depress the circulation are not 
great. In Archangclsky's experiments the chloral concentration of 
the blood of dogs lying in profound sleep lay between 0.03 and 0.05 
per cent., while when this concentration reached 0.056 per cent, the 
blood-pressure had fallen to one-half of its original height, and with 
a concentration of 0.07 per cent, cessation of respiration occurred. 
[Clinical experience with this drug indicates very clearly that the 
dangers of harmful depression of the circulation, when chloral is cor- 
rectly used, have been greatly over-estimated. The figures quoted above 
of a concentration of 0.03-0.05 per cent, in the blood, in no way 
correspond to the concentrations which can be produced by any 
ordinary doses. — Tr.] 

Relaxation of the vessels results in a slowing up of the blood flow 
throughout the body, and, if this lasts for any considerable time, in 



CHLORAL HYDRATE 91 

patients with respiratory disturbance it may lead to cyanosis and even 
cedema of the lungs, while, in addition, the decided direct depression 
of the respiratory centre produced by chloral hydrate warns one to 
exercise caution in its use in such patients. 

With continued use there is danger of habituation. Another reason 
why abuse of this drug is dangerous is that chloral hydrate may cause 
a parenchymatous degeneration of certain of the important organs, 
in which particular its effect is similar to that of prolonged chloroform 
anaesthesia. 

When this occurs, the decomposition of proteids is augmented, just as 
occurs in phosphorus poisoning. However, the breaking down of the proteids 
does not proceed to the normal final stages, but stops with the formation of 
some more complicated intermediate decomposition products, whose nature is 
still unknown but which are probably substances resembling the peptones 
( Harnack ) . 

Toxicology. — Especially when first introduced into practice 
numerous acute medicinal poisonings by chloral hydrate resulted from 
its administration in too large doses, and, as a« result of its continued 
use as a sedative, cases of chronic chloral habit developed, particularly 
in insane asylums. To-day medicinal poisonings have become far less 
frequent, but it is frequently employed for suicidal purposes. Cases 
of fatal poisonings have been observed after doses not exceeding 
4.0 gms. 

Acute Poisoning. — The symptoms of acute poisoning correspond 
in general with those of too deep anaesthesia and coma, which have 
already been described in connection with poisoning by other narcotics. 
In these cases the symptoms of insufficient respiration and marked 
impairment of the circulation develop early and the body temperature 
falls. If the drug be very rapidly absorbed, death may ensue very 
quickly as a result of a direct paralytic effect on the heart, and the 
patient may suddenly collapse. When the absorption has taken place 
more gradually, coma and complete anaesthesia with abolition of the 
reflexes develop, and death results from cessation of the respiration, 
the heart action also being extremely feeble. In contrast to the usual 
behavior of the pupils in morphine poisoning, they are widely dilated 
in chloral poisoning, and, with equally deep coma, the circulation is 
much more markedly depressed by chloral hydrate, while the respira- 
tion remains relatively good much longer than is the case in morphine 
poisoning, in which the respiration is alarmingly depressed before the 
circulation is markedly affected. 

The TREATMENT OP ACUTE CHLORAL POISONING consists first in 

removing the poison by washing nut the stomach. Emetics cannot be 
used for this purpose, for they will necessarily fail to act, on account 
of the depression of all reflexes, including those which bring about 
emesis. In severe poisoning artificial respiration mus1 he instituted. 
As long as this is not necessary the effort is made to maintain the 



92 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

functions of the vasomotor and respiratory centres by various stimu- 
lating agents. For this purpose one uses, as in other narcotic poison- 
ings, sensory stimuli, subcutaneous injections of solutions of caffeine, 
preparations of camphor and of atropine. [Caffeine, in the form of 
strong hot coffee by mouth and by rectum, is used almost as routine.. 
Strychnine subcutaneously appears also to be of distinct value, and 
epinephrin intramuscularly or intravenously, as also heat, certainly 
appears to be indicated. — Tr.] 

Chronic Poisoning. — In chronic chloral poisoning disturbances 
of the digestive organs of most various nature, as well as vasomotor 
and psychical disturbances, occur. Affections of the skin are also very 
common. In general, the clinical picture resembles that of chronic 
morphinism. "When the attempt is made to give up the drug, various 
uncomfortable symptoms and disturbing conditions develop, among 
them great nervousness, anxiety, and insomnia. 
BIBLIOGRAPHY 

Archangel sky: Arch. f. exp. Path. u. Pharm., 1901, vol. 4G. 

Hammarsten, cited from Hermann: Lehrb. d. exp. Toxikologie, Berlin, 1874, 

p. 271. 
Harnack u. Remertz: Fortschr. d. Med., 1893, vol. 11, No. 7. 
Kiilz. E.: Pniiger's Arch., 1882, vol. 28, p. 506. 
Liebreich: Das Chloralhvdrat ein neues Hypnoticum und Anaesthetieum, Berlin, 

L869. 
Musculus u. Mering: Bericht d. Dentsch. chem. Gesellsch., 1875, vol. 8, p. 640. 
v. Mering: Zeitschr. f. physiol. Chem., 1882, vol. 6, p. 480. 
Stintzing; Pentzoldt u. Stintzing's Handb. d. spez. Therap. 

OTHER HYPNOTICS OF THIS GROUP 

The various disadvantages of chloral hydrate soon made it desirable 
to search for substitutes with similar hypnotic action unaccompanied 
by the undesirable side actions, and, as a result, the number of hyp- 
notics of the alcohol group, which have been introduced and which 
are still widely used, has become extremely large. This is in itself 
evidence that none of these hypnotics is ideal, possessing all the proper- 
ties wished for. "With some, the disagreeable taste and odor, — e.g., 
paraldehyde, — witli others, unfavorable behavior in respect to absorp- 
tion and excretion, — e.g., sulphonal, — are unavoidable drawbacks. Still 
others possess the disadvantage that when repeatedly administered 
habituation readily develops, while with others harmful side actions 
occur when they are used continually. 

On the other hand, the different types of insomnia and the variable 
individual susceptibility toward the different drugs are responsible 
for the practical demand for numerous hypnotics, for the undesirable 
side actions of the different hypnotics are of greater or less moment 
according to varying pathological conditions in which they may be 
employed. Furthermore, the harmful effects of the continued use of 
one drug often render it necessary that a change be made from one 
hypnotic to another. 



CHLORAL DERIVATIVES 93 

If one surveys the whole group of hypnotics which have been intro- 
duced since chloral hydrate, the empiric rule may be formulated that 
those hypnotics which contain no halogen, in general, affect the heart 
and the vessels less than do those containing these elements. This 
conclusion corresponds entirely with that formed from practical experi- 
ence with the general anaesthetics. As a result, with the halogen-free 
hypnotics there is a greater difference between those doses sufficient to 
produce sleep and those which unfavorably affect the circulation and 
respiration. 

Chloralamide. — Substitutes for chloral hydrate, which contain the 
molecule of this uncommonly active substance in combination and 
from which the chloral may be set free in the body, will consequently 
possess no essential advantages over chloral hydrate itself. This holds 
true for the widely used chloralamide, which is formed by the union 
of chloral with formalin according to the following formula : 

CCL.CHO + H.CONH 2 = CCl 3 CH(OH)N(CHO)H. 

This drug occurs as crystals, soluble in water in the proportion of one part 
in 20, which are not irritating and which possess a slightly bitter taste. The 
absence of irritating action in the stomach and the slight taste are the chief 
advantages which it possesses as compared with chloral hydrate, but the effective 
hypnotic dose is one and one half times as large as that of chloral. Sleep is 
usually produced from % to 2 hours after its administration. 

Dormiol. — Another combination of chloral with dimethylethylcar- 
binol (amylene hydrate), dormiol, has recently been introduced and 
recommended (Fuchs u. Koch). This amylene chloral is an oily 
water-clear fluid with a smell resembling that of camphor. It may be 
administered in gelatin capsules containing 0.5 gm. In dosage of 0.5- 
1.5 gm. it induces sleep after i/> to 1 hour, which is not accompanied 
by harmful side effects {Peters). [Later experience with this drug 
has shown that this claimed freedom from harmful side actions has 
not been justified. — Tr.] 

Jsopral. — Another hypnotic containing chlorine, isopral, or trichloriso- 
propyl alcohol (Impens), has been rather widely used. This drug is readily 
soluble and easily absorbed, sleep usually following in % to y 2 hour after its 
administration in dosage of 0.5 to 1.0 gm. (Urstein) . Although its toxic action 
on the heart is slight, experiments on animals show that it, too, depresses the 
blood-pressure. Caution is consequently necessary in connection with its use 
in the presence of circulatory disease. [Hatch&r has demonstrated that the claims 
made for its relatively slight toxicity as compared with chloral are not 
correct. — Tr.] 

BIBLIOGRAPHY 

Fuchs u. Koch: Miinchn. med. Woch., 1898, No. 37. 
Impens: Therap. Monatsh., 1903, pp. 409 and 533. 
Peters: Miinchn. med. Woch., 1900, No. 14. 
Urstein : Therapie d. Gegenwart, 1904, p. 04. 

Paraldehyde. — The first hypnotic of this group which is really 
free from harmful side actions on the functions of other organs was 
introduced by Ccrvello in 1883. [This freedom from harmful actions 



94 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

is only a relative one. — Tr.] This is a polymeric modification of the 
common aldehyde CH 3 .COH, three molecules of which are combined 
in it. 

It is a clear, colorless, readily inflammable fluid with a characteristic 
odor and burning taste, rather soluble in water (1 to 8), and easily absorbed, 
so that sleep quickly follows its administration, often within 10 to 15 minutes. 
It is a powerful narcotic, with little harmful action on the respiration, circu- 
lation, or metabolism. In essential insomnia, doses of about 3.0 gm. are usually 
efficacious, and even with long-continued employment of such doses no dangerous 
side effects result. [This statement is not strictly correct, for the literature 
contains more than one reference proving that the contrary may at times be 
true. — Tr.] In extreme insomnia the dosage must be increased up to 4-G gm., 
but much larger doses (even as much as 30-60 gm. ) have been taken without 
dangerous results (Bumke 1 ) . According to many observers, habituation to 
paraldehyde is readily acquired, just as is the case with alcohol, but this cer- 
tainly is not always the case (Bumke, 2 Stintzing) . The only disadvantage of 
this relatively harmless and efficient drug is its disagreeable taste, which is best 
disguised by red wine or tea, and its odor, which resembles that of fusel oil, 
and which, on account of its slow excretion by the lungs, is apparent in the 
breath even on the day following its administration. 

BIBLIOGRAPHY 

1 Bumke: Miinehn. med. Woch., 1002, No. 47, p. 1958. 

2 Bumke: Monatschrift f. Psychiatr. u. Neurol., vol. 12. 
Cervello: Arch. f. exp. Path. u. Pharm., vol. 16, p. 265. 

Stintzing: Penzoldt-Stintzing's Handb. d. Ther. d. inn. Krankh., vol. 5, p. 396. 

Amylenc hydrate, dimethylethyl carbinol, is a tertiary alcohol of 
the amyl series — 

CH,\ 

C H 3 ^C-OH 

C2H5/ 

It is a colorless, oily, rather soluble (1 to 8) fluid, with a disagreeable odor 
resembling that of paraldehyde. In respect to the intensity of its hypnotic power 
it lies between chloral hydrate and paraldehyde, — 1.0 gm. chloral hydrate = 2.0 
gm. amylene hydrate = 3.0 gm. paraldehyde. Like other amyl compounds, such 
as the so-called fusel oils, which in general exert a more powerful effect on 
the nervous system than the ethyl combinations, — e.g., ethyl alcohol, — amylene 
hydrate also produces more marked depression of the circulation than does 
paraldehyde. However, in this respect amylene hydrate has the reputation 
of being less open to objection than choral. The usual dose is 2.0 gm., 4.0 gm. 
being the maximal single dose. It may be administered in gelatin capsules or in 
solution by mouth or by rectum. This drug possesses the disadvantage that 
even hypnotic doses may cause a condition resembling alcoholic intoxication, as 
it strongly excites the motor centres, so that in animals restlessness or even 
severe convulsions may result from its administration in poisonous doses 
(llarnack u. Hermann Meyer), 

Urethan is satisfactory in respect to its freedom from disagreeable 
side actions, as well as in respect to its solubility, taste, and odor. In 
experiments on animals it shows itself to be an extremely good hyp- 
notic which even in strongly hypnotic doses does not impair the heart 
action at all (Schmiedcbcrg). Its hypnotic power in man is, however, 
weak and uncertain, so that it has not been able to establish itself 
as useful. 



SULPHONAL AND TRIONAL 95 

Chemically it is the ethyl ester of carbaminic acid — 

/NH 2 

° = ( \0C 2 H 5 

It occurs as colorless and odorless crystals readily soluble in water, with a salty 
taste. For adults the dose is 2.0-4.0 gm. 

Hedonal. — Under the name of Hedonal, Dreser has introduced another hyp- 
notic belonging chemically to the same class as urethan. In it the ethyl radical is 
replaced by a methylpropylcarbinol radical 

/NH 2 

XO-Cf-CHs 

X G,H 7 

It occurs as colorless crystals, soluble with difficulty in water, and with a 
somewhat disagreeable taste resembling that of peppermint. It is best adminis- 
tered in powdered form in wafers, and, in doses of from 1.0-2.0 gm., produces 
a much more powerful hypnotic effect than ethyl urethan (urethan). This drug 
has been highly praised by some authors, but, according to E. Milller, it appears 
to be unreliable in cases of slight insomnia and often to fail even when larger 
doses are given. It appears to have no dangerous side actions, but at times a 
pronounced polyuria caused by it interferes with the sleep. It also appears 
that habituation readily occurs with both hedonal and urethan. 

BIBLIOGRAPHY 

Dreser: Versamml. d. Xaturforscher und Arzte, 1899. 
Harnack u. Herm. Meyer: Ztschr. f. klin. Med., 1894, vol. 24, p. 374. 
Miiller. E.: Munchn. med. Woch., 1901, No. 10, p. 383, here compl. lit. 
Schmiedeberg: Arch. f. exp. Pathol, u. Pharm., 1885, vol. 20, p. 203. 

Sulphonal and trional have apparently been more widely em- 
ployed as hypnotics than almost any other drugs. The hypnotic actions 
of these disulphones was accidentally discovered by Baumann and 
East in certain physiological experiments instituted with another 
object. 

Chemically sulphonal (sulphonmethane, U.S.P.) is diethyl- 
sulphonedimethylmethane, (CH 8 ) 2 = C =(SOoC 2 H 5 ) 2 , and occurs as 
colorless, tasteless crystals, very slightly soluble in cold water (1 to 
500). When administered as a powder in doses of 1.0 to 2.0 gm. 
(4.0 gm. [ ? Tr.] maximal single dose) together with a sufficient quan- 
tity of warm fluid, sleep usually results after the lapse of 1-2 hours. 
On account of its relative insolubility, its effects are produced not 
only slower than is the case with other hypnotics, but they last longer, 
on account of the slowness with which it is decomposed and excreted. 
After waking there is slight dizziness, and on the following day the 
patient is often drowsy. 

Trional and tetronal are analogous substances, in which ethyl 
radicals replace one or both of the methyl groups of sulphonal and 
which are more active than their mother substance. 

Trional (diethylsulphonemethylothylmethane), or Bulphonethyl- 
methane, is at present preferred by most authorities to sulphonal, 
because, as it is more soluble than sulphonal, sleep is more rapidly 



96 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

induced, and because the factors determining its decomposition and 
elimination are more favorable (Morro). Doses of 1.0-1.5 gm. cause 
sleep after 14 to y 2 hour. 4.0 gm. [ ? Tr.] is the maximal single dose. 

In proper doses sulphonal and trional produce no harmful effects 
on the circulation, respiration, or digestion. After larger doses or 
after continued use of small doses, however, they may cause poisoning, 
evidenced by disturbances of the digestive organs, the metabolism, and 
the central nervous system. Single closes produce such symptoms 
of poisoning only when the usual dose has been very largely exceeded. 
This holds true especially for the relatively less poisonous trional 
{Robert). 

Trional, like sulphonal, often produces a satisfactory hypnotic effect 
even in the second night, this after-effect proving that a certain quan- 
tity of the drug still remains in the body in a form which is still 
active. The harmful effects of both of these drugs also are due to this 
persistent after-effect, the danger of cumulation being greater with the 
less readily decomposed sulphonal than it is with trional. The majority 
of the numerous cases of poisoning produced by these drugs, which 
formerly were frequently observed as a result of their careless 
employment (especially with sulphonal), occurred when they were 
administered during too long a period (lit. Friedlander, v. Taylor and 
Sail). 

East states that in man the dosage of sulphonal should not exceed 
2.0 gm., and in women, who are much more readily poisoned, it should 
not exceed 1.0 gm., and that, when used for a long time, its adminis- 
tration should be discontinued in periods of one to several days. With 
trional also daily administration is not permissible, and even with 
men the doses should not exceed 1.25 gm. 

In sulphonal poisoning the symptoms consist in persisting con- 
fusion, ataxia, constipation, vomiting, and abdominal pain, and also 
in symptoms of irritation of the kidney, albuminuria and nephritis. 
In the majority of cases there is also a peculiar decomposition of the 
haemoglobin, resulting in the appearance of hcematoporphyrin in the 
urine. The reddening of the urine thus caused, while not constant, is a 
very frequent symptom of sulphonal or trional poisoning, and, as this 
symptom is often one of the first to develop, it may serve as a warning. 
Consequently, whenever these drugs are continually administered, the 
urine should be regularly examined. Thus far we know nothing of 
the manner in which hcematoporphyrinuria is produced. It may be 
experimentally produced in rabbits but not in dogs (Neubauer). 

BIBLIOGRAPHY 
Baumann u. Kast: Zeitschr. f. pliysiol. Chemie, 1890, vol. 14. 
Friedlander: Therap. Monatsh., 1894, pp. 183 and 370. 
Kast: Arch. f. exp. Path. u. Pharm., 1892, vol. 31, p. G9. 



VERONAL GROUP 97 

Kast: Berl. klin. Woch. u. Therap. Monatshefte, 1888. 
Kobert: Lehrb. d. Intoxikationen, 2d edition, Stuttgart, 1906. 
v. Mering: Therap. Monatsh., 1896, p. 421. 
Mono: Deutsche med. Woch., 1894, No. 34 and 46. 
Neubauer: Arch. f. exp. Path. u. Pharrn., 1900, vol. 43, p. 456. 
v. Taylor u. Sail: neurol. Zentralbl., 1901, No. 11, p. 516. 

Veronal. — Comparatively recently, diethylbarbituric acid, veronal, 
and dipropylbarbituric acid, proponal, have been introduced as hyp- 
notics and have very rapidly been extensively employed (E. Fischer 
and v. Mering). 

Veronal, 

CHsXp/CO-NHXp 
CHs/ °\CO-NH/ CU ' 

occurs as a crystalline powder, soluble with difficulty in water, and with a 
slightly bitter taste. The mean hypnotic dose is 0.5 gm., but with women doses 
of 0.25-0.3 gm. are often sufficient. As far as may be judged from the reports 
at present available, it is a reliable and, in proper dosage, harmless hypnotic. 
However, it appears that its use is not unattended with danger in case its 
administration is too quickly repeated. [At least tico fatal cases of poisoning 
have occurred after relatively small amounts had been taken. — Tr.] It is 
excreted in unaltered form, but rather slowly (E. Fischer and v. Mering, Aug. 
Iloffmann) , so that prolonged action and rather lasting conditions of confusion 
have often been observed. Its sodium salt, medinal, is more soluble in water, 
and consequently may at times be preferred to veronal. When injected subcu- 
taneously into animals, from 45 to 90 per cent, of the amount administered is 
excreted in the urine, the amount thus excreted varying with the size of the 
dose. It has not been possible experimentally to demonstrate that it produces 
any well-marked cumulative effects (Bachcm.) Following too large doses in a 
number of cases, sleep lasting for days has already been observed. [In animals 
veronal may produce degeneration of the kidney. — Tr.] 

Proponal acts more rapidly than veronal, and 0.35 gm. appears to produce 
about the same effect as 0.5 gm. of veronal (Rumheld). Ziehen warns against 
exceeding the dose of 0.5 gm. 

A ( a tonal. — Still another hypnotic is neuronal, bromdiethylacetamide, 
CBrCCJIJnCOXIL (Fuchs and E. Schultze). This is a powder, soluble with 
difficulty in water, which is effective in doses of from 0.5-1.0 gm. Up to 1905 
there were no reports indicating that it produces any harmful side effects or 
cumulation (Blcibtreu, K. Schultze). 

Bromural. — Krieger and v. d. Velden have reported favorably of their 
experience with bromural, 2 monobrom-isovaleryl-urea, in doses of 0.6-1.0 gm. 
in tin- form of tablets. This drug acts as a mild hypnotic and useful sedative, 
producing its effects fairly rapidly. In experiments on animals a deep narcosis 
may be induced by this drug without harmfully affecting the circulation or the 
respiration. 

BIBLIOGRAPHY 

Bachom: Arch. f. oxp. Path. u. Pliarm., 1910, vol. 63, p. 228. 
Fischer, E., u. v. Mering: Med. Klinik, 1905, No. 52, p. 1327. 
Fischer, E., u. v. Mering: Tlit'rapie d. Gegenw., 1903. 
Fischer, E., u. v. Mering: Therapie d. Gegenw., 1904. 
Fuchs ii. E. Schultze: Mfinchn. med. Woch., L905, No. 50. 
Boffmann, Aug.: Inaug.-Diss., Giesscn, 1906. 
Krieger u. v. d. Velden: Deutsche med. Woch., 1907, No. 6. 
RSmheld: Therapie d. Gegenw., 1906, p. 190. 
Schultze, K.: Therapie der Gegenw., 1905, p. 14. 
Ziehen: Deutsche med. Woch., 1908. 



08 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

THE RELATIONSHIP BETWEEN CHEMICAL CONSTITUTION 
AND PHARMACOLOGICAL ACTION 

In this section only those members of the alcohol group have been 
discussed which have been widely employed as anesthetics or hypnotics. 
There is a very much larger number of substances of the alipathic 
series which possess more or less marked pharmacological actions of 
this nature, and consequently, as may well be understood, many 
attempts have been made to determine the relation between the con- 
stitution of these hydrocarbons, alcohols, aldehydes, ketones, sulphones, 
esters, etc., and their pharmacological actions. As a result, a number 
of laws or principles have been discovered, with the aid of which it 
has been possible to make certain deductions which have rendered 
possible a successful search for new active substances. 

In general, substances in which the alky] radicals are attached to tertiary 
or quaternary carbon atoms are more active than the analogous combinations 
containing the carbon combined with only one or two other carbon atoms. For 
this reason, the primary alcohols produce less narcotic effect than the secondary 
ones, and these in turn less than the tertiary alcohols (v. Hering and Sohnee- 
gans). Further, in general the law holds good, that ethyl groups, if attached 
to carbon, endow substances with more pronounced narcotic properties than do 
methyl groups in the same situation. Thus, for example, ethyl alcohol is more 
strongly narcotic than methyl alcohol, v. Mering and Schneegans have found 
that in the series of tertiary alcohols 

CH 3 \ CH 3 \ CsHX 

CH 3 )C-OH CH 3 ^C-OH C 2 hAc-OH 

CH 3 / C2H5/ GH5/ 

trimethyl carbinol, dimethylethyl carbinol, and triethyl carbinol, the hypnotic 
action increases according to this law, the hypnotic dose in rabbits for these 
three substances being respectively 4.0, 2.0, and 1.0 gm. Baumann and East 
have shown a similar relationship between the narcotic power and the number 
of the ethyl radicals contained in the molecules of the members of the sulphone 
series, in which the attachments of alkyl radicals to the sulphone radicals which 
are attached to the quaternary carbon appear to have the same significance as 
their direct attachment to the carbon atom. 
Sulphonal 

CH 3 \ /S0 2 .C 2 H 5 

CH 3 /^\S0 2 .C 2 H 5 

is consequently approximately as active as dimethylsulphonediethylmethane 

C 2 H 5 \ /S0 2 .CH 3 
C 2 H 5 / L/ \S0 2 .CH 3 

The analogous substance containing only methyl groups, dimethylsulphonedi- 
methylmethane, 

CH 3 \ /S0 2 .CH 3 

CH 3 /^ \S0 2 .CH 3 

is inactive, but, on the other hand, trional, which contains three ethyl radicals, 
is more active than sulphonal, while tetronal, diethylsulphonaldiethylmethane, 

C2H 6 \ /S0 2 .G.H 5 
C 2 H 6 / U \S0 2 .C 2 H 6 , 



c 

CHEMICAL CONSTITUTION; PHARMACOLOGIC ACTION 99 

which contains four ethyl groups, is still more active. This relationship between 
the activity of the substance and the number of ethyl groups holds good, how- 
ever, only for a certain intramolecular arrangement of the atoms, such as is 
present in sulphonal. Even in such disulphones as contain the sulphone radical 
attached to different carbon atoms, as, for example, in ethylenediethylsulphone, 

CH 2 -S0 2 .C,H 5 
I 
CH.-SCX.GHs, 

the ethyl groups no longer produce these effects (Baumann and East). 

This law, therefore, holds good only within certain limits, the introduction 
of other groupings into the molecule lessening the importance of the ethyl radicals 
or entirely abolishing it. Notwithstanding this, the deduction that the com- 
bination of ethyl groups with a tertiary or quaternary carbon atom results in 
especially powerful hypnotic powers, has pointed out the path to the synthesis 
of other hypnotics, — for example, to that of veronal (Fischer u. v. Mering) . 

The introduction of halogen atoms attached directly to carbon increases 
the narcotic power of substances already possessing such powers. Thus, the 
narcotic effect of the hydrocarbon methane, CPL,, is extremely slight, but, with the 
successive substitutions of chlorine for its hydrogen atoms, its narcotic action is 
augmented, chloroform, CHC1 3 , being more active than bichlormethane, CH 2 CL, 
which in turn is more active than methylchloride, CH 3 C1. However, the introduc- 
tion of chlorine atoms, as a rule, also endows the substance with toxic side 
actions on the heart and vasomotor, centres, a fact to which attention has already 
been directed in connection with the comparison of ether with chloroform, and 
also in connection with the comparison of chloral hydrate with alcohol and the 
chlorine-free substitutes for chloral hydrate. As a result of the study of these 
relationships, it is clearly evident that not only the intensity of the narcotic 
actions but also the character or quality of pharmacological actions may be 
changed by the introduction of chlorine atoms (Kionka) . For example, the 
introduction of still another chlorine atom into chloroform transforms this sub- 
stance into tetrachlormethane, CC1 4 , which is a convulsant poison (v. Ley). The 
strengthening influence of the introduction of the halogens may also be demon- 
strated when bromine atoms are substituted in hydrocarbons (Fuclis it. Schultze, 
v. d. Eeckout). 

The narcotic power of trichloracetic acid when compared with that of the 
corresponding aldehyde, chloral, is very slight. This will serve as an illustration 
of the general law that the introduction of acid radicals weakens or abolishes 
the narcotic activity of various atom groups. 

The investigation of the relationship between chemical constitution 
and pharmacological action in the alcohol group has thus led to the 
conclusion that the entrance of certain atoms and atom groups into 
certain active compounds augments or weakens their activity. There 
is si ill lacking, however, an explanation why the ethyl groups, for 
example, increase the activity of the substances only when they are 
introduced into substances of certain definite configuration and do 
not augment the activity of other molecules with another configuration. 
It is certain that the ethyl groups themselves do not independently pro- 
duce these effects, for those substances whose activity is attributable to 
the ethyl groups — such, for example, as the disulphones (Diehl) or 
ethyl alcohol — certainly produce their effects before, and not after, 
they have been decomposed. The ethyl groups, therefore, do not pro- 
duce their pharmacological effects after they have been split off from 
the whole complex. If, therefore, the number of them present in 
the molecule determines the degree of its activity, this is only to be 



I 

100 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

understood on the assumption that the entrance of the ethyl groups 
into the molecule endows it with certain chemical or physical proper- 
ties which are responsible for the narcotic action. This also holds true 
for the augmentation of physiological activity resulting from the 
introduction of halogen atoms, for chloroform during narcosis is 
excreted almost entirely in unaltered form, being decomposed scarcely 
at all in the body. The setting free of chlorine, therefore, cannot 
be the cause of this so strikingly augmented physiological activity 
of chloroform as compared with its chlorine-free mother substance, 
methane. 

An instructive example of these relationships is also presented by 
the halogen substitution products of isovalerylurea. In the cold- 
blooded animals the chlorine, bromine, and iodine substitution products 
of 1h is substance are much more strongly narcotic than is the halogen- 
free mother substance. As, however, the halogen is present in a suffi- 
ciently firm combination only in the chlorine and bromine substitution 
products, and as the iodine substitution product is decomposed and 
rapidly loses its iodine at the temperature of warm-blooded animals, 
this last combination behaves quite differently in the warm-blooded 
animals than do the other two, being no more active at this higher 
body temperature than is the halogen-free mother substance (v. d. 
F.i ckhout ) . It is thus clear that the halogen in the molecule augments 
its activity only so long as it is able to influence the properties of the 
whole atom complex. 

BIBLIOGRAPHY 

Baumann u. Kast: Zeitschr. f. physiol. Chemie, 1899, vol. 14, p. 52. 

Diefal: Inaug.-Diss., Marburg, 1894. 

v. d. Eeckhout: Arch. f. exp. Path. u. Pharm., 1907, vol. 57, p. 338. 

Fischer u. v. Mering: Therapie d. Gegenw., 1903. 

Fuclis u. Schultze: Miinchn. med. Wochenschr., 1904, No. 25. 

Bildebrandt: Arch. f. exp. Path. u. Pharm., 1905, vol. 53. p. 90. 

Kionka: Arch, intern, de Pharmacodyn. et de Therap., vol. 7, p. 476. 

v. Ley: Inaug.-Diss., Strassburg, 1889. 

v. Mering u. Schneegans: Therap. Monatsh., 1892, p. 327. 

THEORY OF NARCOSIS 

A theory of narcosis formulated by Hans Meyer 1 and Overton, 
which may now be discussed, permits us to determine which physical 
or chemical properties of the narcotics are responsible for their 
activity and to leam in what fashion these properties are modified 
by the presence of certain radicals in the molecule. 

As early as 187G, Buchheim 1 defined the aim and task of pharma- 
cologists as consisting, first, in determining at which point in the body 
a drug acted, and, second, in explaining such actions by a reaction 
between the cell constituents and the drug. This second problem, that 
of showing how the pharmacological actions are due to the properties 
of the chemical substances which produce them and to their action on 



THEORY OF NARCOSIS 101 

the cells affected, has, up to the present time, been successfully solved 
in a few instances only, of which carbon dioxide poisoning is one. 
Conditions similar to those involved in the reaction between carbon 
dioxide and haemoglobin may also be assumed to explain the elective 
action of curarine and other ammonium bases on motor nerve-endings 
(Fiihner). However, the formation of a chemical combination be- 
tween the drug and some constituent of the protoplasm, which (after 
the analogy with the action of carbon dioxide) we are justified in 
assuming, may in many instances be assumed only in the case of 
such foreign substances as are chemically active. 

Among the narcotics of the aliphatic series, on the other hand, 
there are many chemically entirely inactive substances which exert a 
characteristic narcotic action on the nervous system. If we wish to learn 
which of their properties are responsible for the pharmacological 
actions exerted in common by the narcotics of this series, which in 
their chemical behavior differ from each other so decidedly, we must 
look for those properties common to all of them, — to those among them 
chemically least active, for example, the saturated hydrocarbons; as 
well as to those chemically most active, for example, the aldehydes, 
such as choral hydrate. 

Lipoid Solubility. — It has been found that all possess the physical 
property of being soluble in both water and fats. This especial 
solubility in fats, associated with a sufficient solubility in water, is 
essential for the absorption of the narcotics by the cells and is respon- 
sible for their peculiar distribution in the different tissues of the body, 
and by the physical-chemical theory of narcosis explains the pharma- 
cological action of the narcotics. 

As early as 18-47, shortly after the discovery of ether and chloro- 
form anaesthesia, B'ibra and Ilarless sought to explain their anaesthetic 
power as the result of their power of dissolving fat. As a result of 
quantitative determinations of the fat contents of normal and narco- 
tized animals, they believed that they had found out that the anaes- 
thetics actually removed larger or smaller quantities of fat-like 
substances from the brain. They assumed, consequently, that these 
drags were responsible for a sort of extraction of fat-like substances 
from tin' brain, and considered that this was the cause of anaesthesia. 

However, there can be no question of such extraction of the fat- 
like constituent of lie' nerve-cells, for this would be inconsistent with 
the characteristic rapid restoration of function which follows interrup- 
tion of anaesthetization. 

"Hermann investigated the hsemolytic action of ether, chloroform, etc., and 
explained this by their power of dissolving the lecithin of the red blood-cells, 

and drew a parallel between tins and the narcosis of the central nervous system 
w itii its large content of lecithin. 

These two hypotheses, therefore, contained the correef central idea 

of explaining the nareotie action of various drugs by their common 



102 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

property of ready solubility iu the fats, for they produce their effects 
on the central nervous system because they go into solution in the 
fat-like constituents, the lipoids, of nervous tissues, and form a 
physical-chemical combination with them. 

Elective Absorption by the Nervous System. — Long ago, Buck- 
It i iiit - stated clearly that the pharmacological actions affecting chiefly 
the nervous system were to be considered as the result of reactions 
with those cell constituents "which are peculiar to the nervous system 
or which occur chiefly there." As a matter of fact, the central nervous 
system differs from other tissues especially in the large quantity of its 
fat-like constituents. A substance foreign to the body, moreover, can 
produce a pharmacological action only where it is absorbed in sufficient 
quantities by the cells. Consequently, a necessary primary condition 
for the elective action of the narcotics on the nervous system is its 
sufficient absorption by the functional elements. Narcotic substances 
must first of all be neurotropic, in the sense in which this expression 
was first employed by Ehrlich. 

Ehrlich 1 was the first to attribute the absorption and storing up of various 
substances by the nervous system to their affinity to its lipoid constituents, and 
especially to emphasize the importance of studying the distribution in the body 
and in various organs of pharmacologically active substances. For such investi- 
gations he employed chiefly dyes, the distribution of which is so readily apparent 
after intravital staining or so readily demonstrable by various reactions. Start- 
ing with these ideas, he demonstrated that the majority of the basic dyestuffs, 
which are absorbed by the brain, are also stored up in various other fatty tissues. 
Neurotropism and lipotropism thus go hand in hand. If now a sulphonic acid 
radical was introduced into a neurotropic dyestuff, its distribution in the body 
was found to be entirely altered, the dyestuff losing its neurotropic properties 
as a result of the introduction of the acid radical; and Ehrlich drew the parallel 
between this observation and the fact that neurotoxic substances, such as phenol, 
certain alkaloids, etc., as a rule lost their toxicity as a result of the introduction 
of the sulphonic acid radical and at the same time lost their neurotropic 
character. 

Ehrlich' was thus able to demonstrate for the dyestuffs the manner in 
which their affinity, and thus their power of penetrating into the nervous cells, 
was altered by certain changes in their constitution, and to show that, as a 
result, their distribution in the tissues was a factor having an important bearing 
upon the relationship between chemical constitution and pharmacological action. 

The ready solubility of the narcotics in fatty substances conse- 
quently determines the manner in which they are distributed in the 
various organs and cells. This solubility in fats is also a prime 
requisite for the absorption of foreign substances by all cells. Overton 
has proved, for the majority of organic substances, that the greater 
their solubility in fat, as compared with their solubility in water, the 
more rapidly do they penetrate into the protoplasm. He, consequently, 
assumed that the protoplasmic membrane is impregnated with certain 
substances, the lipoids, which possess solution affinities similar to those 
of the fats. 

Tn addition to a solubility in fat, a certain solubility in water is 
also essential if a substance is to be absorbed. Substances which are 



THEORY OF NARCOSIS 



103 



entirely insoluble in water and which are also not volatile are either 
split up in order that they may be absorbed, as is the case with the 
fats, or, like paraffin, they are not absorbed. 

Distribution of Naecotics in the Organism. — The distribution 
of a substance throughout the body is, therefore, determined not only 
by its solubility in fats, but by its relative solubility in fat and in 
aqueous media. That, as a matter of fact, the narcotics, when dis- 
tributed about in the body, are absorbed to the greatest extent by those 
cells and organs in which fat-like substances preponderate, is shown 
by the following facts : Chloroform is present in larger quantities in 
the red blood-cells than in the serum, because lecithin and cholesterin, 
chloroform-soluble constituents of the erythrocytes, absorb it in rela- 
tively larger quantities (Pold). Ether, chloral hydrate, and acetone 
are distributed in the same unequal fashion between the blood-cells 
and the plasma {Frantz, Archangelsky) . The distribution of these 
various substances in the different organs of the body follows the same 
law of distribution. The accompanying table gives the results of 
Nicloux's investigation of the distribution of chloroform. 

Distribution of Chloroform in Ancesthetized Dogs (Nicloux). 





Duration of anaesthesia 




30 min. 


30 min. 


84 min. 


SO min. 




Per cent. 

0.0525 
0.059 

0i047 

0.0465 

0.0335 

o!6i5 

0.049 

.... 


Per cent. 

0.070 

0.0555 

0.085 

0.083 

0.0505 

0.0465 

0.038 

0.041 

0.0215 


Per cent. 

0.064 

0^0545 

0.0795 

0.0805 

0.0525 

0.046 

0.031 

0.0395 

0.0245 

0.037 

0.068 

0.132 


Per cent. 




0.049 




0.046 


Medulla 


0.075 


Cord 






0.0485 




0.039 




0.031 




0.039 








0.265 




0.0685 




0.0875 







From this table it is apparent that certain portions of the nervous 
system, a.s well as those deposits of fat which are well supplied with 
blood, eontain larger amounts of chloroform than do the other organs. 



Fatty tissues are thus soon to compete especially with the nervous system 
in respect to the absorption of chloroform, and. as a matter of fact, Mamsfeld 1 
lias recently shown that certain internally administered narcotics act more 
powerfully in emaciated than in well-nourished animals, and that their brains 
contain almost (wire as large a portion of the chloral hydrate administered as do 
those of well-nourished animals, in which the fatty tissues ahsorh a portion of 
the narcotic. Such comhinations between these narcotics and this tissue (the 



104 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

fat), as also their combination with other pharmacologically less susceptible 
tissues, — e.g., the liver, — do not produce readily appreciable results, for the 
narcosis of the liver-cells or of the red blood-cells does not at once express itself 
by any change in function, and an acute injury of these less susceptible cells will 
evidently be produced only by a concentration which would already have caused 
death by its actions on the nervous system. [Such effects are probably produced 
not infrequently during ana-sthesia. The destruction of the red cells almost cer- 
tainly occurs in varying degrees under varying clinical conditions, and acute 
degeneration of the liver, which not infrequently has followed chloroform anaea- 
thesia, would appear to be a late expression of such action. — Tr.] 

Solubility Reactions with the Lipoids. — Certain observations on 
the absorption of dyes by vegetable cells (Pfeffer) and by colloidal 
substances, such as gelatin plates (Hofmeistcr) , furnish some data 
which help us in understanding' or imagining the fashion in which 
the "solution affinity" of the narcotics for the lipoids determines the 
proportions in which they accumulate in the different tissue cells. 
These dyestuffs pass from dilute aqueous solutions and accumulate in 
vegetable cells or gelatin plates in much greater concentration, forming 
firm physical combinations or solutions with the colloidal contents of 
these cells or plates if they possess a solution affinity for them, — that 
is to say, if they are more soluble in these colloids than in water 
(Spiro). Under such conditions one may observe an elective absorp- 
tion, some dyestuffs being rejected and the others continuing to be 
absorbed until a condition of equilibrium has been established, which 
corresponds to a certain distribution coefficient between the colloid 
and water. If now the colored vegetable cells or gelatin plates are 
transferred to water containing no dye, the dyestuff gradually passes 
back again into the water. The process is thus a reversible one. The 
absorption of the narcotics by the lipoids of the nervous system which 
occurs during the narcosis, and the restoration of function after the 
narcotics have been eliminated from the blood may be considered 
to take place in a similar fashion, the whole process corresponding 
entirely with the chemical extraction by agitation of a substance which 
is soluble in different degrees in two media w T hich are not miscible with 
each other. 

Narcosis the Result of this "Solution Reaction." — From the 
above discussion, it is apparent that the distribution of the narcotics 
in the body and their elective accumulation in the nervous system are 
dependent on their "solution affinity" to the lipoids. The theory 
of narcosis, however, does not stop here, but goes one step farther and 
endeavors to explain the action of the narcotics as due to this solution 
reaction. According to this theory, the absorption of the narcotics 
is not merely a preliminary condition necessary for the occurrence of 
some still unknown reactions between the narcotics and other con- 
stituents of the cells, but this "solution reaction" with the lipoids of 
the nerves is the essential cause of the narcotic action. This con- 
clusion has been reached as a result of determining the quantitative 



THEORY OF NARCOSIS 



105 



relationship between the degree of activity of the narcotics and their 
distribution coefficient between water and fats. 

It is naturally impossible actually to determine these distribution 
coefficients between the lipoids of the brain and the blood-plasma 
which, according to the theory, will determine the degree of the nar- 
cotic power. Consequently, we must be satisfied with an approximate 
expression of the solution affinity of the narcotics for the lipoids of 
the nervous system on the one hand and the aqueous body fluids on 
the other. The distribution coefficient between oil and water may 
be considered as such an approximate expression, and Hans Meyer x 
and Overton have determined these coefficients for a very large number 
of otherwise indifferent narcotic substances, and have compared them 
with the narcotic power of the different substances, which is expressed 
by the smallest molecular concentration sufficient to narcotize small 
tadpoles or fishes swimming in the solutions. The threshold value for 
the appearance of the narcosis may be quite exactly determined by this 
method, because a constant condition of equilibrium is established 
between the solution containing a certain amount of the drug and the 
animals swimming about in it. For example, in a solution containing 
one and one-half per cent, of ethyl alcohol, tadpoles are completely 
narcotized in 2-3 minutes, and a narcosis of constant degree is main- 
tained for hours. In a 1 per cent, solution, on the other hand, no 
complete narcosis results, even when they remain therein for days. 

The comparison of the distribution coefficient with the degree of 
the narcotic action of the different substances shows that the molecular 
concentration sufficient to produce narcosis diminishes with almost 
complete regularity as the coefficient of distribution increases. The 
narcotic power thus increases with the relative solubility in fat as com- 
pared with the solubility in water, as is shown by the accompanying 
examples : 





Distribution coefficient. 

Solubility in fat 

Solubility in water 


Effective molecular 
concentration 


Trional 


4.4 

4.0 

1.1 

0.7 

0.22 

0.14 

0.03 


0.0013 
0018 


Suphonal 

Bromal hydrate 

Chloral hydrate 


0.006 
0.002 
0.025 
025 


Alcohol 


0.5 



A further proof that the narcotic powers of these drills stand in 
u regular relationship to their distribution coefficients has been fur- 
nished by a series of experiments in which a comparison was made of 
the narcotic power of certain substances at different temperatures, 



106 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 



certain drugs being used whose coefficients of distribution between oil 
and water were distinctly altered by the changes of temperature (Hans 
Meyer 2 ). 





Threshold of narcotic 
action, effective dilution 
of the normal solutions 


Partition coefficient 

Solubility in fat 
Solubility in water 




At 3° Q. 


At 30° C. 


At 3° C. 


At 30° C. 




1 : 1300 
1 :500 
1 :90 

1 :3 
1 :50 
1 :3 


1 : 600 
1 :200 
1 :70 

1 : 7 
1 :250 

1 :7 


2.23 
0.67 
0.093 

0.024 
0.053 
0.140 


1.40 




0.43 




0.066 


Ethyl alcohol 


0.046 


Chloral hydrate 


0.236 
0.195 







With three of these substances the distribution coefficient is in- 
creased by heating from 3° to 30°, while with three others the opposite 
effect is produced. Entirely in accordance with this increase or 
diminution in the relative solubility in fat, the narcotic power of the 
substances rises or falls, so that, for example, tadpoles at 30° C. are 
just narcotized by a certain concentration of chloral hydrate, but wake 
up again when the solution is cooled and are again narcotized when 
the solution is again warmed. 

By these investigations proof has been furnished for the causal 
relationship between the narcotic action of certain indifferent lipoid- 
soluble substances and the power of the nervous system to attract and 
retain them. However, there are still differences of opinion as to the 
significance of these relationships. There are those who have been 
willing to see in the cell lipoids of the nervous system only the solvent 
which brings the narcotics into contact with the functioning nucleus 
of the susceptible cells, where they are able to react with other 
constituents of the cells which are still entirely unknown to us. 
According to this conception, assumed that this attraction and 
retention are essential preliminary conditions for the pharmaco- 
logical action, and that, for example, increasing temperature 1 , by alter- 
ing the solution affinity, will be accompanied by a similar change in 
the degree of the pharmacological action. However, the very extensive 
quantitative parallelism between the pharmacological power of. the 
different narcotics and their coefficients of distribution is not suffi- 
ciently explained by this assumption, for if the contact action, which 
cannot be followed further, is assumed to take place between the 
narcotics which have penetrated into the interior of the cells and an 
unknown substance or mixture of substances, one would be forced 
to conclude that the .strength of this contact action is necessarily 
quantitatively alike with the different narcotics, otherwise the paral- 



THEORY OF NARCOSIS 107 

lelism between the narcotic power and the concentration in the cell 
lipoids could not be maintained. If one, however, assumes that the 
narcotics and some unknown constituents of the nerve-cells — for 
example, the proteids — enter into a physical-chemical reaction, on 
the degree of which the narcotic activity must depend, this hypothe- 
tical reaction would necessarily follow the same scale of chemical 
relationship as do their soluble affinities to fats. In other words, these 
hypothetical cell constituents must also possess lipoid properties; 
otherwise the narcotic power could not remain parallel with the dis- 
tribution coefficients of solubility in fats. Consequently, we see in the 
lipoids of the nerve-cells not merely substances which act as the means 
of bringing about a solution of the narcotics in the cells, but we see 
in them the actual substance or substances which are acted upon by the 
narcotics. As a result of their loose physical-chemical combination 
with the narcotics, these lipoids lose their normal relationship to the 
other cell constituents, and as a result the entire chemism of the cell 
is inhibited. 

Among the results of this inhibition is a diminished absorption or utiliza- 
tion of oxygen, which has been shown by Verworn and his collaborators to occur 
in narcosis. This deprivation of oxygen by itself produces a depressing or 
paralytic effect very much in the same way as does narcosis ( Mansfeld 2 , 3 ) . The 
inhibition of oxidation is, therefore, certainly a factor accompanying chloroform 
or ether anaesthesia which tends to augment the narcosis, but, just as certainly, 
it is not the cause of the anaesthesia, for vital phenomena, such as nervous 
excitation, are inhibited only by many times greater degrees of narcosis than are 
necessary to cause an inhibition of the consumption of oxygen {Dontas, Eober, 
Warburg 1 , 2 ) , and, furthermore, narcosis inhibits those very phenomena of life 
for which energy is not furnished by oxygen (Winterstein) . 

There has been a wide-spread tendency to assume that the pro- 
teids alone are essential factors in the functional activity of cells, 
but the general occurrence of lecithine and other lipoids in all living 
cells speaks against this view. It appears that these substances do 
not play in the cell a role of reserve substances as do the true fats, but 
that they are combined intimately with proteid to form a portion of the 
functioning protoplasm. Combinations of lecithin and proteid, how- 
ever, manifest similar solution affinities to those of lecithin and must, 
therefore, in their relationship to this narcosis theory, be considered 
as lipoids. 

The fact that the narcotics of this series possess the power of 
paralyzing not only nervous elements but also all living cells is quite 
in accord with ibis general distribution of the lipoids in all cells. 
That the narcotics are primarily neurotoxic is due to the fact thai the 
disturbance of function which they cause expresses itself most clearly 
in the nervous organs. 

Side Actions of these Drugs. — This theory of narcosis is based 
on the presumption thai further investigations will confirm this paral- 
lelism between the anaesthetic power and the partition coefficient of 



108 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

solubility in the lipoids and the plasma. In no case, however, is an 
absolute parallelism to be expected, for the partition coefficient be- 
tween oil and water is only an approximate expression for the actual 
distribution of the anaesthetics between the cerebral lipoids and the 
blood-plasma. Above all, it is only with those members of this group 
which are chemically indifferent and which do not readily enter into 
chemical reactions that one may assume an absence of affinities for 
ether constituents of the nervous tissues. As a matter of fact, the 
various side actions of the different narcotics indicate clearly that 
such side reactions also occur. However this may be, the basic narcotic 
action of the different members of the alcohol-chloroform group is, 
in principle, so similar, that we are compelled to assume that it is 
caused by a reaction which is common to them all. The more, however, 
the essential pharmacological actions of narcotic substances differ from 
the typical action of this group, the more necessary is it to assume that 
other reactions are involved in producing their atypical actions. Thus, 
for example, phenol, as a lipoid soluble substance, might be considered 
as belonging to this group, and, as a matter of fact, it does produce 
some narcotic effects, but, as it possesses strong affinities for proteids 
and other constituents of the body, it also produces its own peculiar 
pharmacological effects. 

Other Types of Anaesthesia. — This theory cannot by any means 
be used to explain every kind of anaesthesia, for many other quite 
different disturbances of the chemical equilibrium of the nerve-cells 
must inhibit their functions and produce superficially similar symp- 
toms, as is, for example, the case with the salts of magnesia 
(Meltzer V) . The method of action described above applies, there- 
fore, only to chemically relatively indifferent substances. 

In this sense, substances such as free C0 2 and N0 2 which chemically 
do not even remotely resemble the members of the aliphatic series, may 
also be considered as belonging pharmacologically to the group of 
alcohol, for they act as narcotics and are soluble in the lipoids, while 
the carbonates, which do not produce such effects, are also insoluble 
in the lipoids. On the other hand, it is in the highest degree probable 
that besides being soluble in the lipoids the alkaloids possess other 
affinities for other cellular constituents, for the manifold character 
of their pharmacological actions of itself indicates that they must act 
on different constituents of the nerve-cells. The alkaloidal drugs do 
not exhibit such a uniform type of pharmacological action as do the 
members of the alcohol group, as is shown by the fact that not all types 
of cells are pharmacologically influenced by them, numerous vegetable 
cells, for example, being entirely unaffected, a fact which by itself 
renders it improbable that their fundamental action is due to their 
affinity to the lipoid substances, w r hich are such universal constituents 
of cells. 



CENTRAL DEPRESSANTS 109 



BIBLIOGRAPHY 



Arehangelsky : Arch. f. exp. Path. u. Pharm., 1901, vol. 46. 

Bibra u. Harless: Ueber die Wirkung d. Schwefelathers. 

1 Buchheim: Arch. f. exp. Path. u. Pharm., 1876, vol. 5, p. 272. 

2 Buchheim: Arch. f. Heilkunde, 1870, vol. 11. 

Dontas : Arch. f. exp. Path. u. Pharm., 1907, vol. 59, p. 430. 

^hrlich: Therap. Monatsh., March, 1887. 

2 Ehrlich : Festschr. f . Leyden, 1898. 

Frantz: Inaug.-Diss., Wiirzburg, 1895. 

Fiihner: Arch. f. exp. Path. u. Pharm., 1908, vols. 58 and 59. 

Hermann: Arch. f. Anat. u. Physiol., 1866. 

Hober: Z. f. allgem. Physiol., 1910, vol. 10, p. 173. 

Hofmeister: Arch. f. exp. Path. u. Therap., 1811, vol. 29. 

1 Mansfeld: Arch. int. de Pharmacodynamie et de Ther., 1905, vol. 15; 1907. 

vol. 17. 
2 Mansfeld: Pfluger's Arch., 1910, vol. 131, p. 457. 
"Mansfeld: Pfliiger's Arch., 1909, vol. 129, p. 69. 
Meltzer, J., u. J. Auer: Am. Journ. of Phys., 1905-06, vols. 14, 15, 16; Journal 

of Exp. Med., 1906, vol. 8. 
1 Mever, Hans : Zur Theorie d. Alkoholnarkose, Arch. f. exp. Path. u. Pharm., 

1899, vol. 42. 

- Meyer, Hans: Arch. f. exp. Path. u. Pharm., 1901, vol. 46. 
Nicloux: Les Anesthesiques generaux, Paris, 1908. 
Overton: Studien iiber die Narkose, Jena, 1901. 

Pfeffer: TJntersuchung a. d. botan. Inst., Tubingen, 1866. 
Pohl: Arch. f. exp. Path. u. Pharm., 1891, vol. 28. 
Spiro: Habilitationsschrift, Strassburg, 1897. 
Verworn: Deut. med. Woch., 1909, No. 37. 
'Warburg: Miinchn. med. Woch., 1911, No. 6. 

- Warburg: Z. f. physiol. Chem., 1910, vol. 69, p. 452. 
Winterstein: Z. f. allgem. Physiol., 1907, vol. 6, p. 315. 

OTHER CENTRAL DEPRESSANTS 

In this chapter mention has been made only of the therapeutically 
most important of the many organic drugs which exert pharmacological 
actions on the central nervous system. Such actions of numerous 
other drugs will be described in connection with the discussion of 
their other more important actions on other organs. Other drugs, 
again, which act primarily and chiefly on the central nervous system 
possess only a toxicological significance, although among them are some 
which formerly were widely used in medicine, but which are to-day 
used so seldom that they may be dismissed with a few words. 

Aconite, the root of Aconitum napellus, or monkshood, is such a 
drug, which is official and is still quite extensively used, particularly 
by the homoeopaths.* 

The various aconitines on the market differ quite markedly from one 
another, but are all esters of various aconines with acetic, benzoic, and other 
acids. Locally applied, they cause a primary stimulation followed by a later 
depression of the sensory nerve-endings, causing first a feeling of warmth and 
tingling and later anaesthesia. Repeated administration of doses of 1—2 nig. 
causes paresthesia, formication, and numbness of the extremities, with diminution 
or complete abolition of sensations of pain, such as those of neuralgia. These 



110 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

systemic effects are probably tbe result of their action on the central nervous 
Byatem or on the spinal ganglia ( Wartmann, Colin). Toxic doses are followed by 
convulsions, due to asphyxia, and by paralysis and death. Even very small doses, 
mere fractions of a milligram, may cause serious symptoms, and 3-4 mg. of 
aconitine nitrate may cause death. The cases of poisoning which have been 
reported have usually been due to the variable strength of the different aconitine 
preparations {Kunkel, Kornaletoski) . 

BIBLIOGRAPHY 

Cohn: Diss.. Berlin, 1888. 

Kornalewski: Ztschr. f. Medizinalbeamte, 1904, p. 4G9. 

Kunkel: llandh. d. Toxikol.. 1901, p. 67. 

Wartmann: Diss., WUrzburg, 1883. 

Numerous inorganic substances also exert toxic actions on the 
central nervous system, and even those salts which are normal con- 
stituents of the body may produce these effects if, as a result of their 
intravenous or subcutaneous administration in too large quantities, 
the normal equilibrium of the different ions is disturbed. 

Magnesium salts occupy a peculiar position among the salts, 
causing, without any primary stimulation, an elective paralysis of the 
central nervous system, the heart being hardly at all affected by 
them and the muscles retaining their excitability (Meltzer and Alter 1 ). 
It appears tbat Mg ions, which in relatively small amounts are normal 
constituents of the tissues, when present in sufficient concentrations 
abolish the excitability of all nervous organs. In the frog a curare- 
like paralysis of the motor nerve-endings is the most striking effect 
produced (Binet). This effect is produced also in warm-blooded 
animals, but, as it occurs later than does the stoppage of the respira- 
tion, it can be observed only if artificial respiration be carried on 
I Wihi). This effect on the respiration is preceded by complete anaes- 
thesia, paralysis of the higher motor centres, and depression of the 
blood-pressure {Meltzer and Aucr 2 ) . The vagus nerve-endings also lose 
their excitability, and the motor and sensory nerve-trunks, if brought 
in direct contact with magnesium salts, lose their conductivity. Quite 
recently these actions have been utilized in practice (Meltzer) [but, 
with the exception of the local anaesthetic actions, apparently with little 
success. Injected intradurally, solutions of magnesium salts cause a 
spinal analgesia resembling that produced by cocaine, but more lasting. 
Practical experience with this method has, however, shown that it is 
attended by such danger that it has been abandoned, at any rate for 
the present. — Tit.]. 

All the toxic symptoms produced by magnesium salts may be 
caused to disappear promptly by the intravenous injection of calcium 
salts (Meltzer and Alter '■'■), calcium ions appearing to act antago- 
nistically to those of. magnesium and to be able to restore the equi- 
librium between the various ions when it has been disturbed by an 
excess of Me ions. 



THE BROMIDES 111 

BIBLIOGRAPHY 

Binet: Revue medic de la Suisse romane, 1892, p. 523. 

Meltzer: Berl. klin: Woch., 1906, No. 3. 

i Meltzer, S. J., u. J. Auer: Am. Journ. of Physiol., 1905-06, vols. 14, 15, and 16. 

2 Meltzer, S. J., u. J. Auer: Journ. of Exp. Med., 1906, vol. 8. 

3 Meltzer, J., u. J. Auer., Am. Journ. of Physiol., 1908, vol. 21, p. 400. 
Wiki: Journal de physiologie et pathol. generale, 1906, No. 5. 

Potassium salts do not cause such a well-developed elective 
paralysis, but when administered intravenously or subcutaneously 
they exert toxic actions both on the nervous system and on the heart. 
[It is in the highest degree improbable that the medicinal adminis- 
tration of potassium salts ever produces such a "potassium" toxic 
action. The common belief that potassium salts are "too depressing" 
is based only on a misinterpretation of experimental evidence. — Te.] 

THE BROMIDES 
The anions of neutral salts, particularly Br ions, may also exert 
specific therapeutically useful actions on the nervous system. As these 
salts in their pharmacological actions show a certain resemblance to 
the hypnotics, it is appropriate to take up their discussion at this time. 
In the body the bromides of the different alkaloids produce entirely 
similar pharmacological effects, and consequently their pharmacological 
actions must be attributed to their bromine component and not to 
their different metallic components (K, Na, etc.). 

Soon after Ballard in 1820 discovered bromine and the bromides, KBr 
was employed in therapeutics, at first as a substitute for KI, which chemically so 
closely resembles it. Very soon its uselessness in lues was recognized, but 
at the same time its efficiency as a sedative for the central nervous system became 
apparent. In 1864 it was first used by Behrend in certain forms of sleepless- 
ness, and a little later by Vigouroux and Voisin in epilepsy. 

Action of Large Doses in Health. — Concentrated solutions of the 
bromides irritate the tissues chiefly as a result of their salt action, 
but dilute solutions produce no marked irritation and are rapidly 
absorbed. In man very large doses (10 gm.), in addition to causing 
a salty after-taste in the mouth and a feeling of pressure and warmth 
in the epigastrium, cause a certain amount of stupor, with disturbance 
of the powers of perception as well as of the speech. Besides this, such 
doses cause a very complete abolition of the reflex irritability of the 
palate and posterior pharyngeal wall, so that gagging does not follow 
mechanical irritation (Kross). The bromides are not to be considered 
true li.\ [Miotics, for in man therapeutic doses of 1-2 gm. do not produce 
;i condition resembling normal sleepiness and fatigue. It is in accord 
with this that in experiments on animals no narcosis results from the 
administration <>f; the bromides, but only a diminution of the centra] 
reflex excitability when large doses arc given. Eowever, in slates <>F 
nervous excitemenl and in epilepsy their administration produces a 
quieting or sedative effect. 



112 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Thus far we have no knowledge of the details of the manner in 
■which these effects are produced. Psycho-physical analysis has shown 
only that the hromide salts influence those psychic processes which may 
be experimentally measured, in a very different fashion from the true 
hypnotics, for doses of 2-4 gm. neither impair the perception of 
sensory stimuli nor the inauguration of motor acts (Lowald). On the 
contrary, intellectual work is favorably influenced by the bromides, 
particularly if the performance of such work has been rendered diffi- 
cult as the result of pronounced feelings of discomfort. It, therefore, 
appears that under such circumstances bromides eliminate certain cen- 
tral excitations, which accompany feelings of discomfort and which 
interfere with the performance of mental work. 

In conditions op disease also, the bromides act favorably upon 
such conditions of nervous hyperexcitability as are accompanied by 
discomfort or malaise, as is often the case in neurasthenia and epilepsy. 
Bromides also often produce sedative and hypnotic effects in conditions 
of hyperexcitability in arteriosclerotic patients (Ilomburgcr), but, on 
the other hand, they are ineffectual in such conditions as simple mani- 
acal excitement (Lowald). It, therefore, appears that, when potas- 
sium bromide is administered in the usual hypnotic and sedative doses 
of 1-2 gm., its effects are due to a very specific action on the cerebral 
cortex. 

Action in Epilepsy. — The diminution of the reflex excitability of 
the central nervous system, which may be demonstrated experimentally 
after large doses of bromides, appears to be of significance in con- 
nection with the use of KBr in the treatment of epilepsy, in which it 
is administered in daily dosage of 5-10 gm. or more, amounts which 
even in normal individuals exert a distinct influence on the cerebral 
sensory and motor functions. 

In experiments on animals, Albertoni has shown that large but non- 
toxic doses of KBr, especially when administered repeatedly, markedly 
lessen the electric excitability of the cerebral motor centres. While 
in the normal controls stimulation of the cortex with electric currents 
of a certain strength always caused general epileptiform convulsions, 
showing that the stimuli spread from the directly stimulated centres 
over the whole motor region, in the bromiclized animals no generalized 
convulsions occurred, but only clonic movements of the muscles whose 
motor centres lie close to the stimulated points. This is best explained 
on the assumption that the drug blocks or renders difficult the passage 
of impulses along (he paths which connect the various motor centres. 
While there can be no question of the favorable influence exerted by 
the bromides on the number and intensity of the epileptic attacks, 
we cannot obtain any closer insight into the manner in which they do 
so until the cause of epilepsy is more completely understood. 

Pretention in the Body. — The favorable therapeutic effects of the 
bromides do not become manifest until a rather high degree of satura- 



THE BROMIDES 113 

tion of the organism has been produced, and when this occurs the effect 
in diminishing the epileptic attacks persists for some time after cessa- 
tion of medication. This is due to the fact that bromides are not 
completely eliminated in the 24^36 hours following their ingestion, 
but that, in spite of the fact that their elimination starts almost 
immediately, only from one-tenth to one-fourth of the amount adminis- 
tered is excreted in the first 24-36 hours, and that even 20 days after 
cessation of its administration it has not been completely eliminated 
{Fere, Hebert et Peyrot, Nencki, Pflaumer). It is thus evident that 
the organism retains large amounts of bromides for a considerable 
period (v. Wyss 1 , 2 E. Frey). 

As a result of this retention when bromides are regularly ingested, 
a certain saturation of the organism results. While at the start 
from 10 to 48 per cent, of the daily dose is ehminated, the amount 
varying with the amount of urine excreted, the percentage eliminated 
increases from day to day, so that when, for example, 7 to 8 gm. of 
XaBr are taken daily for two weeks or so, a state of bromine equilib- 
rium results, in which the elimination and absorption of bromine are 
equal {Laudenheimer, v. Wyss, 1 ? Fessel). 

When bromides are taken regularly, the blood always contains 
bromides, and the chlorides are correspondingly diminished, so that 
when saturation has been produced % to % of the CI of the blood- 
serum has been replaced by Br {Laudenheimer, v. Wyss, 1 ? Ellinger) . 
The bromides also partially replace the chlorides in other tissues, 
accumulating in the largest amount in those organs which normally 
are richest in chlorine, in which they to a certain extent assume the 
role of chlorides. For instance, HBr appears in the gastric juice 
{Kiilz, Nencki). According to Hoppe, the percentage of HBr in the 
gastric juice may serve to indicate the degree of bromine saturation 
which has been attained. 

If this replacement of chlorides by bromides occurs to too great 
a degree, toxic symptoms appear, in which case the free administra- 
tion of common salt is curative (v. Wyss 1 ' 2 ), as it accelerates the 
elimination of the bromides and replaces the bromides in the tissues 
and body fluids {Laudenheimer, Ellinger). 

It is of practical importance to remember that the accumulation of 
bromide in the body is influenced by the amount of NaCl ingested, for 
the curative effects in epilepsy are obtained more rapidly and with 
smaller doses if the diet be one poor in salt {Richct). Bromism, too, 
occurs more rapidly with such diet. 

The following figures, from Ellinger and Kotake, show how in rabbits the 

elimination of hromides is augmented l>y the simultaneous administration of 
Na< 1 and not hv that of the other salts, and also show how the hlood contains 

larger amounts of bromides when the diet is poor in NaCl than when this salt is 
administered freely. 



114 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

XaBr-XaCl Experiment. XaBr-Xa Acetate Experiment. 

Constant diet — 0.322 gm. XaBr and Same diet and 0.322 gm. XaBr and 
2.0 gm. NaCl daily for G days 2.0 gm. sodium acetate for 6 days 

Total Br excreted 
0.74 gm. 0.41 gm. 

Blood on Gtli day contains 

0.064 per cent. Br = 9.52 per cent 0.1G per cent. Br = 23.8 per cent. 

of the total halogen mols. 

A comparison of the following two experiments shows A'ery strikingly 
how the bromine saturation when once attained is rapidly lessened by the 
administration of XaCl and how this salt, in contrast to other salts, accelerates 
the elimination of Br in the urine. 

Period I. 
Rabbit A: Rabbit B: 

For 8 days 0.322 gm. XaBr daily and For 8 days 0.322 gm. XaBr daily and 
no NaCl. no sodium acetate. 

Urine on 7th and 8th days contains 

CI 0.G7 gm.; Br 0.28 gm. = 15.3 per CI 0.56 gm.; Br 0.26 gm. = 16.8 per 
cent, of the total halogen mols. cent, of the total halogen mols. 

Blood on the 8th day contains 

CI 0.22 per cent.; Br 0.15 per cent. = CI 0.23 per cent.; Br 0.16 per cent. = 
23.8 per cent, of the total halogen 23.8 per cent, of the total halogen 

mols. mols. 

Period II. 

For four days 0.322 gm. XaBr + 2.0 For four days 0.322 gm. XaBr + 
gm. XaCl daily 2.0 gm. sodium acetate daily 

Urine on 1st and 2d days contains 

CI 2.52 gm.; Br 0.51 gm. = 7.7 per CI. 0.G7 gm. ; Br 0.26 gm. = 15.3 per 
cent, of the total halogen mols. cent, of the total halogen mols. 

Blood on the '4th day contains 

CI 0.28 per cent.; Br 0.064 per cent. CI 0.24 per cent.; Br 0.18 per cent. = 
= 9.2 per cent, of the total halogen 23.9 per cent, of the total halogen 

mols. mols. 

Bromism. — The accumulation in the body of excessive amounts of 
bromides would appear to explain the undesirable bromide actions 
which at times are observed. In milder cases these affect chiefly the 
skin and mucous membranes, causing various exanthematous eruptions, 
usually an acne, but in severer cases causing pustular eruptions. 
Coryza, conjunctivitis, aud catarrhal inflammations of the respiratory 
tract also occur. These lesions are probably all due to irritation caused 
by the bromides or their transformation products during their excre- 
tion by the glands of the skin and mucous membranes, where, probably 
under the influence of acid secretions, hydrobromic acid is formed, 
which is readily decomposed, liberating free bromine. As bromine is a 
powerful irritant to the tissues, it is easy to understand how the 
local lesions are produced. It is probable that the gastro-intestinal 
disturbances, which are often observed in cases of chronic bromism and 



THE BROMIDES 115 

which cause emaciation and cachexia, are dependent on the excretion 
of the bromides through the alimentary mucosa. Disturbances of the 
central nervous system, leading to loss of memory and apathy and to 
motor and sensory disturbances, may also be observed. Nad may be 
used as an antidote in such conditions.* 

Preparations. — For therapeutic purposes the bromides of the alkalies are 
the preparations most used. Those most commonly used are potassium bromide 
(67 per cent. Br), sodium bromide (77 per cent. Br), and ammonium bromide 
(81 per cent. Br), which are all colorless crystalline powders very soluble in 
water, and with a salty, rather disagreeable taste. With the two first named 
no qualitative or quantitive differences are observed in their pharmacological 
action, except that the sodium salt is slightly more powerful on account of its 
larger bromine content. With large doses of ammonium bromide the local and 
systemic actions of its basic component are evident. In order to avoid gastric 
irritation, these salts should be administered well diluted with water. 

With the idea of avoiding the undesirable effects of the bromides a num- 
ber of organic bromine compounds have recently been introduced, for which 
various advantages have been claimed. In judging of these claims it must not be 
forgott&n that these organic compounds contain much smaller quantities of 
bromine than the inorganic bromides, which probably explains their slighter 
toxic power [and also their slighter therapeutic efficiency. — Tr.] Among these 
may be mentioned: Bromipin, brominized sesame oil, obtainable in two strengths, 
10 per cent, and 33% per cent. Br; sabromin, dibrombehenate of calcium, contain- 
ing 29 per cent. Br; and bromine compounds with albumin, such as bromeigone 
(11 per cent. Br), or with gelatin, such as bromocoll (about 20 per cent. Br). 
Up to the present neither clinical experience nor experimental evidence has 
demonstrated that these preparations possess any real superiority to the bromide 
salts {Bilinski, Hermann) . 

Valerian is another drug producing mild hypnotic effects, which, although 
no longer so highly esteemed as formerly, is still often used in hysterical patients. 
As the active constituents of the drug are very unstable, its galenic preparations 
are of uncertain and variable potency. 

The active constituents which are present in the oil of valerian exert some 
narcotic action on the cord and the higher cerebral centres (Binz, Grisar) . From 
it there have been isolated borneol and the bornyl esters of different fatty acids, 
particularly isovalerianic acid, which esters, like the crude drug, exert a distinct 
depressing action on the central nervous system (Kionka). Borneol isovalerate 
under the name of bornyval, and a mixture of menthol witli the menthyl ester 
of valerianic mid under the name of validol, have been introduced as substitutes 
for the crude drug or its galenic preparations, but they too are unstable and, 
like isovalerianic acid itself, are likely to prove inactive (Kochmann) . Perhaps 
valwl, valerianic acid diethylamide, is the beat of these substitutes for the 
crude drug. It appears to act as a mild hypnotic and sedative. 

BIBLIOGRAPHY 

Albertoni: Arch. f. exp. Path. u. Pharm., 1.8S2, vol. 15, p. 248. 

Behrend, Henri: banc. May. ]S(i4, p. 607. 

Bermann: Therap. Monatshefte, April, L910. 

Bilinski: Therap. Monatshefte, February, 1910. 

Binz: Arch. f. exp. Path. u. Pharm., 1876, vol. 5, p. 10!). 

Ellinger u. Kotake: Med. Klinik, 1910, No. 38, p. 1474. 

Fere. Herbert et Peyrot: Compt. rend de la. Bociete" de Idol., 1802, p. 513. 

* r. li'i/v.s- - attributes Hie toxic effects of (he bromides to the diminished 
chloride content of the blood and nut In the accumulation of the bromides. 
According to this view, (he curative action of Hie free administration of sodium 
chloride is due not to Hie removal of the excess of hromides hut to the making 

good of the chloride deficit. 



116 PHARMACOLOGY OF CENTRAL NERVOUS SYSTEM 

Fessel: Mflnchn. med. Woch., 1800, p. 1270. 
Frey, H.: Zeitschr. f. exp. Path. u. Therap., 1010, p. 401. 
Grisar: Inaug.-Diss., Bonn, 1873. 
Griinwald, Zentralbl. f. Physiol., 1908, vol. 22, No. 16. 
Bomburger: Therap. d. Gegenw., 1904, p. 302. 
Bondo: Berl. klin. Woch., 1902, p. 205. 
Boppe: Zentralbl. f. Xeurologie, 190(1, ]». 994. 
Kionka: Arch. int. de Pharmacodynamic, 1904, vol. 13, p. 215. 
Kochmann: Deutsche med. Woch., 1904, p. 57. 
Kross: Arch. f. exp. Path. u. Pharm., 1877, vol. G, p. 1. 
Kiil/. B.: Zeitschr. f. Biol, 1887, vol. 23, p. 4G0. 
Laudenheimer : Neurol. Zentralbl., 1897, p. 538. 
Laudenheimer: Neurol. Zentralbl., 1910. p. 461. 
Lowald: Kriipelin's psychophysische Arb., vol. 1, No. 4. 
Nencki u. Schoumow-Simanowsky: Arch. f. exp. Path. u. Pharm., 1894, vol. 34, 

p. 313. 
Pflaumer: Diss., Erlangen, 1896. 

Richet et Toulouse: Compt. rend de l'acad. des sciences, 1899, vol. 129, p. 850. 
Vigouroux: i'-;r/.. <lcs hdpitaux, 1864. 
A'oisin: Bull, de therapeut., 1866. 

1 v. YYvss: Arch. f. exp. Path. u. Pharm., 1906, vol. 55, p. 266. 
= v. Wyss: Arch. f. exp. Path. u. Pharm., 1908, vol. 59, p. 186. 



CHAPTER III 

PHARMACOLOGY OF THE SENSORY NERVE-ENDINGS 

The end-organs of the sensory nerves are everywhere exposed to 
the pharmacological action of chemical substances. 

Stimulation of the sensory nerves expresses itself as pain, as a 
feeling of heat or cold, etc., which often excite reflexes, as, for example, 
when stimulation of the sensory nerves of the stomach causes vomiting 
or when irritation of the trigeminal terminations in the nasal mucous 
membrane produces sneezing. With the corrosives, the stimulation 
of the sensory nerve-endings is only a symptom of the general action 
on all tissues which results in the death of the cells. There are, 
however, certain substances, such as veratrine, which exert an abso- 
lutely specific action on these organs. 

Keflex Effects of Sensory Stimulation. — In collapse and in 
narcotic poisoning, agents stimulating these organs are frequently 
employed to produce a reflex stimulation of the depressed respira- 
tory and circulatory centres. For such purposes mechanical (fric- 
tion, slapping, etc.), thermic, or chemical irritation of the skin may 
be employed. As chemical irritants or stimulants only such agents 
may be used as penetrate the horny epidermis with sufficient rapidity 
to reach the sensory end-organs, volatile substances, such as mustard 
oil or acetic ether, being best adapted for such purpose. Reflexes 
from sensory irritation without doubt play an important role in 
producing the effects caused by the subcutaneous injection of cam- 
phor and of ether, especially in the latter case. Olfactory stimu- 
lation, as by ammonia, and stimulation of the taste, as by the ethers 
of wines with strong bouquet, are other examples of sensory stimula- 
tions, which refiexly affect the respiration and circulation. 

LOCAL ANESTHESIA 

This depends on the feasibility of temporarily depressing the 
cxcil ability of sensory nerve-endings without permanently damaging 
them, and in recent years its field of usefulness has been steadily 
widened. 

Local anaesthesia may be induced by suppressing the excitability 
of tlic si' usury nerve-en dings, "terminal an.kstjiksi \," or by prevent 
ih>_r (be conduction of nervous impulses in the nerve-trunks, "nerve 
BLOCKING." The blocking of the centripetal sensory fibres may occur 
at any point between the point at Avhich the posterior roots enter the 
cord and the terminal end-organs. AVhen it is the mure delicate ter- 
minal nerve-fibres which are affected, it, is difficult In distinguish the 
effects of such action and those resulting from depression of the 

117 



118 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

terminations of the nerves. [As a matter of fact, both the terminal 
organs and the terminal fibres are usually affected together. — Tr.] 

Anesthetization of the sensory organs may be produced by either 
physical or chemical action. Interruption of sensory conductivity by 
compression is the oldest known method of causing anaesthesia. The 
"going to sleep*' of the extremities, with the resulting paresthesia 
and numbness, which is caused by accidental compression of nerve- 
trunks against bone, is a common experience, and is an illustration 
of anesthesia by compression. In former times surgeons frequently 
induced anesthesia by tightly ligaturing an extremity. [Infiltration 
anaesthesia (see below) depends wholly or in part on the effects of 
compression of the sensory terminal fibres and organs. — Tr.] Neu- 
ralgic pain may often be alleviated temporarily by pressure on the 
trunk of the nerve affected. 

Anesthesia may also be induced by producing a local aislemia. An 
example of this is the anesthesia which soon follows the ligation of a 
large vessel, such as the crural artery, the terminal sensory organs 
being the first structures affected, while the nerve-trunks retain their 
excitability for a long time, even after complete interruption of the 
blood supply. Anemia alone, however, does not induce anesthesia 
quickly enough for practical purposes, but the application of the 
Esmarch bandage favors local anesthesia by causing both compression 
and anemia. As will be seen later, both compression and anemia, 
induced in various ways, are of much value in augmenting and aiding 
the action of cocaine and similarly acting drugs. 

Local Anaesthesia by Cold. — Extreme cold can also render unex- 
ci table both the terminations and the trunks of the sensory nerves, 
as is evidenced by the well-known fact that the extremities become 
insensitive when exposed to ice and snow. 

James Arnott, in 1840, was the first to make a systematic use of cold for 
the induction of local anaesthesia. His method consisted in applying a mixture 
of ice and salt to the skin of the part to be anaesthetized. Richet, in 1859, 
employed the cold resulting from the evaporation of ether for the purpose of 
anaesthetizing the skin, and Richardson, in 18GG, improved the technic by intro- 
ducing the ether spray. 

The lower the boiling point of the evaporating fluid the more 
intense is the cooling of the skin, and, therefore, ethyl chloride, 
which boils at 12.5° C, freezes the skin much more rapidly, and for 
this purpose has almost completely superseded ether. Mixtures of 
ethyl chloride with the gaseous methyl chloride, which boil at 
2-0° C, have been introduced and appear to have advantages as 
means of rapidly freezing tissues. "Anesthyl Bengue" and 
" metathvl limning " are two such preparations. 

When exposed to low temperatures, the smooth muscles and the 
vessels of the skin first contract and the skin becomes pale, but on 
longer exposure reddens. If the temperature be reduced far enough 



LOCAL ANESTHESIA 119 

to freeze the skin, it suddenly becomes white and hard, the blood flow 
ceases, and the sensory nerves lose their excitability, so that the tissues 
become insensitive. The anaesthesia is the combined result of the 
cold and the anaemia. Too long continuation of the freezing may 
result in gangrene. At the start, too rapid freezing causes quite sharp 
pain, but gradual freezing and thawing are painless. The pain preced- 
ing the anaesthesia is therefore less with the ether spray than when 
ethyl chloride is used. [With reasonable care freezing with ethyl 
chloride is practically painless. — Tr.] 

A thorough freezing with complete anaesthesia is attainable only in 
the skin, for the penetration of the effects of cold is limited in tissues 
f reely supplied with blood. Consequently, the more hyperaemic mucous 
membranes may be from inflammation, the more incomplete is the 
anaesthesia from cold. In spite of these drawbacks, freezing of the 
surface often renders good service when small incisions are to be made 
or an abscess opened. Especially is this the case in dental practice. 

LOCAL ANAESTHESIA BY CHEMICAL AGENTS 
Until Roller, in 1884, made known the anaesthetic action of cocaine, 
local anaesthesia was induced only by the methods mentioned above, 
and practically the only method used was that based on freezing. 
The possibility of electively influencing the sensory nerves by chemical 
substances was for the first time demonstrated by the action of cocaine. 
[Aconite and other drugs, however, had long been used to produce 
relative local anaesthesia. — Tr.] 

Any substance, which reacts chemically with the constituents of a 
sensory cell, necessarily causes a change in the constitution of its 
protoplasm and affects its function in some degree and manner. 
Therefore all substances, which, as a part of their general destructive 
action on the tissues, possess strong chemical affinities for the con- 
stituents of protoplasm, cause at first violent stimulation of the sensory 
elements, or pain, and later insensibility or permanent destruction of 
their function. Consequently, true corrosives cannot be utilized to 
induce anaesthesia. As, however, the sensory end-organs are especially 
susceptible, they are affected by very weak concentrations of the 
genera) cell poisons, — e.g., by agents precipitating proteids. In this 
manner certain corrosives in relatively great dilution may induce local 
;ina-Nilic.si;i without necessarily harming other tissue elements. Car- 
BOLIC A.CID is such a substance, which readily penetrates the skin, in 
proper dilutions causing first burning and Later insensibility. Dress- 
ings saturated with 1-2 per cent, carbolic acid solutions, when left 
in contact with the skin, produce a local anaesthesia, but they may also 
cause gangrene. 

A large majority of Ibc snbsijmces which react to any degree with 
the protoplasm of the peripheral sensory oervous elements paralyze 
or anaesthetize these only after first causing irritation and pain. A 



120 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

typical example of such substances is ammonia, which, although it 
specifically paralyzes motor nerve-endings {Griitzner) , first stimulates 
exposed sensory nervous elements and afterwards produces a marked 
anaesthetic effect (Gradenwitz) . Such substances which cause first 
local pain and later local anaesthesia are very numerous, and have 
been named by Liebreich "an^esthetica dolorosa." 

INFILTRATION ANESTHESIA 
The Effects of Anisotonic Solutions. — On account of its rich supply 
of sensory terminal organs, the human skin is the tissue most suitable 
for testing the effects of this procedure (Heinze, Braun *). Solutions 
at the temperature of the body are injected into the skin, causing pale 
wheals to rise above the surrounding skin (Schleich). When thus 
applied, distilled water causes first pain and later insensibility, which 
may last for a quarter of an hour. Addition of salt lessens both the 
primary pain and the anaesthesia, while 0.9 per cent. NaCl solutions, 
which are isotonic with the tissues, can be injected without causing 
pain, but as the concentration is increased above 0.9 per cent, the 
primary pain and the later anaesthesia increase progressively. These 
effects are due either to the swelling up of, or the abstraction of water 
from, the tissue cells, which is caused by the hypotonic or hypertonic 
solution, the former giving off water to and swelling up the cells, 
the latter abstracting it from the cells and causing them to shrivel up 
or shrink. These effects of such solutions, which can be closely fol- 
lowed in vegetable cells, in the erythrocytes, and in other readily 
isolated cells, also occur in the nerve-cells. Braun'sh 2 observations — 
that the "indifferent point," where the least effect was produced, 
was found, with solutions of very different substances, always to coin- 
cide with concentrations isotonic with the blood — indicate clearly that, 
quite aside from the chemical effects of different salts, acids, bases, 
and organic substances, the physical influence of inhibition or of 
abstraction of water can affect the function of the sensory cells. This 
fact is of importance in connection with all injections into the tissues, 
and for this reason Braun insists on the use of osmotically indifferent 
solutions when inducing infiltration anaesthesia by Schleich's method. 
Only in this way may the pain due to the swelling or shrinking of the 
nerve-cells be avoided and the pure cocaine effects be obtained. [In 
infiltration anaesthesia, pressure also plays some role. — Tr.] 

COCAINE 

In contrast to the large number of substances belonging to the 
group of the " anaesthetica dolorosa " is the relatively small number 
of substances which exert an elective action on the peripheral sensory 
elements, and which possess the power of causing a paralysis without 
any marked stimulation of these elements. Cocaine was the first drug 
known to possess such action, but since its introduction a number of 



COCAINE 



121 



drugs have been discovered or synthetized which produce similar effects 
and resemble it more or less closely in their chemical structure. 

Cocaine, first prepared in 1860 by Wohler and his pupils, occurs in the 
coca leaves in the proportion of about % per cent. From the rather insoluble, 
readily crystallized alkaloid, soluble salts may be prepared, of which the hydro- 
chlorate alone is used. It is an ester of complex structure, resembling atropine 
in its constitution. On boiling with acids or alkalies, it splits up into benzoic 
acid, methyl alcohol, and the base, ecgonine, which closely resembles tropine, a 
base which, with tropaic acid, results from the decomposition of atropine. The 
foundation of both the bases is a double ring, which, it may be assumed, is 
formed by the combination of a pyrrolidin ring with a piperidine ring. Ecgonine 
is tropine carbonic acid. The close constitutional relationship between cocaine 
and atropine is well shown in the accompanying graphic formulae. 



H 2 C- 



-CH- 



-CH 2 



> 



H.C- 



-CH- 



-CH 2 



Tropin 



^OH 



H 2 C 



H 2 G 



C< 



COOH 




Ecgonine. 



H 2 C 



H 2 C 




CH- 



C< 



COOCH3 
H 



N(CH 3 ) MX 

/ x O . COC 6 H 5 



CH- 



-CH 2 



Cocaine, benzoylecgonine methyl ester. 

TCenzoyleegonine has no local anaesthetic action for the typical cocaine 
actions develop only when this substance is esterfied, as, for example, by metliy- 
lation. Its ethyl ester and other homologous substances act like cocaine (Pouls- 
son) . The pharmacological activity of the drug depends also on the presence in 
the molecule of the benzoyl radical, for, when other acid radicals are substituted, 
the anaesthetizing action is weakened or destroyed. 

Source. — Cocaine is obtained from the leaves of Erythroxylon 
coca, a plant indigenous in South America, especially in Peru and 
Bolivia, where it was held to be a sacred object and was valued as an 
indispensable stimulant (Genussmittel). The leaves mixed with ashes 
or lime are chewed by the natives, who attribute the most wonderful 
effects to this practice, claiming that it increases the bodily powers 
and renders one more eager for work and more cheerful. Especially, 
however, they believe it to render one more capable of great exertion 
without fatigue and of resisting hunger and thirst. These effects have 
been confirmed by the observations of many travellers. Such reports 
''•<! to repeated investigations of the coca leaves in European lands, 
l'Mf at first only negative results were obtained, as the investigators 
attempted only to determine whether the coca leaves acted as a means 
of lessening combustion in individuals who took their usual nour- 
ishment. 



122 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

Historical. — Therapeutically the most important property of 
cocaine is its paralytic action on the sensory nerve-endings. Step by 
step the induction of local anaesthesia by the use of cocaine has been 
logically developed and has acquired a constantly increasing impor- 
tance for general surgery, until to-day it represents an extremely 
valuable supplement to general anaesthesia. 

The history of the evolution of the knowledge and use of cocaine is a very 
interesting example of the slowness with which an important fact may he recog- 
nized ami of how, after a discovery has been made, a long time may elapse before 
its true significance is appreciated. Wohler, who was the first to prepare cocaine 
in pure form, in his description of its properties, wrote of it: "It tastes bitter 
and affects the nerves of the tongue in a peculiar fashion, so that for a time the 
place of application is benumbed and almost without feeling." The local anaes- 
thesia from chewing the leaves was also noted long ago {de Marie 1862, Scherzer 
1865), while Moreno y Maya in 1868 and v. Anrep in 1880 demonstrated the local 
anaesthetic action in animals, and the latter author demonstrated on himself 
that, by subcutaneous injection of this drug, the skin could be rendered insensi- 
tive to a pin prick. However, it was only after the epoch-making communication 
of the Viennese oculist, Roller, who in 1884 demonstrated its practical value, that 
ophthalmology, laryngology, and other branches of surgery quickly adopted it. 

General Pharmacological Action. — Cocaine is a general proto- 
plasmic poison, which, if absorbed in sufficient amounts, first affects 
the central nervous system. If, however, it is applied locally to the 
tissues and brought in contact with nerve-endings and fibres, its first 
action is that of suppressing the function of the sensory nerve elements. 

It is of fundamental importance for the local action of cocaine that, 
in contrast to most alkaloids, its salts very readily penetrate into 
living cells and thus easily spread into the tissues.* On account of 
the horny nature of its outer coating, human skin is impermeable to 
cocaine, but all living cells readily absorb it, and thus when applied to 
the surface of intact mucous membranes it readily reaches the sensory 
nervous elements. The skin of the frog behaves toward it similarly, on 
account of its numerous glands and the fact that it is constantly moist 
and able to give off or take up gases and aqueous solutions. This 
animal is, therefore, especially adapted for the demonstration of the 
anaesthetic power of cocaine (Grademvitz) . 

Local Anaesthetic Action. — In the "spinal" frog (one in which the higher 
portion of the central nervous system is destroyed) reflexes follow promptly 
on sensory stimulation of the skin, for example on the application of % per cent. 
1K1. If, however, the skin of one leg has been bathed with a solution of cocaine, 
this hg is withdrawn from the acid much later than the other, and with suffi- 
ciently long bathing with cocaine, even the strongest irritation with acid fails 
to produce a reflex movement, for the local anaesthesia is absolute. This experi- 
ment succeeds even better after abolition of the circulation throughout the body, 
for then there is no danger of absorption of enough cocaine to affect the central 

* According to (Iros, cocaine salts do not themselves penetrate the living 
cells, hut the free base is set free by hydrolytic action and enters the cells. Conse- 
quently, the more strongly the salts of the different local anaesthetics are dissoci- 
ated the more powerfully do their solutions act. Gros, therefore, for certain 
purposes recommends the bicarbonate of novocaine as superior to other salts 
formed by it with the strongest acids. (See p. 130.) 



COCAINE 123 

nervous system. The behavior of the other leg which responds normally to irri- 
tation demonstrates that the failure of reflex movements is not due to a paralysis 
of the cord, and the normal motor reaction of the cocainized leg when the other 
leg is stimulated proves that the motor nerves are not affected. 

Besides those of the algesic nerves the nerve-endings of certain 
other sensory nerves are paralyzed, as for example those of the nerves 
for taste, touch, and smell (Zwardemaker), while reflexes from the 
mucous membranes, for example from the conjunctiva, are suppressed 
by its local application. If ammonia be held under a rabbit's nose, 
under normal conditions, the respirations cease in the expiratory 
phase, as a result of a reflex originating in the trigeminal endings in 
the nasal mucous membrane. As cocainization of the nasal mucous 
membrane prevents this reflex (Loewy u. Milller), it has been sug- 
gested that the analogous disturbing reflexes occurring during adminis- 
tration of the general anaesthetics be prevented by a preliminary 
cocainization of the nasal mucous membrane. For operations on the 
larynx and in the nose and pharynx, suppression of the reflexes is often 
of as much importance as is the suppression of the pain sense. 

The anaesthetic action of this drug on the nerve-endings and 
smaller branches is also readily demonstrable in open wounds 
( Griitzner). Best of all, however, it can be shown in the skin, by the 
method mentioned on page 120, where 1 part in 20,000 in 0.9 per cent. 
XaCl solution destroys the sensibility of the wheals for a considerable 
time. The duration of the anaesthesia increases with the concentration 
employed, lasting for 15 minutes with 1 per mille, and for 25 minutes 
with 1 per cent, solutions (Braun, Heinze). The anaesthesia is pre- 
ceded by pain lasting a short time, only when more concentrated solu- 
tions are employed. 

Anaesthesia by Nerve Blocking. — Cocaine is able to penetrate 
through the medullary sheath of nerve-trunks and to suppress their 
conductivity so that the region innervated is rendered anaesthetic 
(regional anaesthesia). The thinner the connective-tissue sheaths 
of the sensory nerves, the more susceptible are they to this blocking. 
Therefore, the finer terminal nerve-fibrils are scarcely less susceptible 
to cocaine than are the nerve-endings. As the drug penetrates more 
slowly into the larger nerve-trunks, a relatively high concentration 
is necessary for their anaesthetization when the injection is made in 
their neighborhood (perineural injection), but with endoneural injec- 
tion even quite dilute solutions quickly induce anaesthesia. 

Elective Action on Sensory Fibres. — Cocaine acts electively on 
the sensory fibres, for, when a solution is applied to a mixed nerve, the 
sensory fibres are more affected than the motor (Alms). 

After 1 minute the conductivity of Hie sensory fibres of the frog's 
sciatic is abolished, while for some time longer motor conductivity 
is unaffected {Kochs). Dixon has confirmed this in the rabbit, and 
Sante8son has shown that contad for 15 to is minutes with a 5 per 



124 PHAKMACOLOGY OF SENSORY NERVE-ENDINGS 

cent, solution of cocaine so completely abolishes sensory conductivity 
of the nerves that even the strongest tetanizing stimulus peripherally 
to the point of cocaine application produces no reflexes, although the 
motor conductivity remains unaffected for about one hour longer. It 
is thus < vidt nt that not only the terminal organs of motor and sensory 
n< riu s r/ act diff( rently to various drugs, — e.g., to curare and cocaine, — 
hut that the two types of nerve-fibres show a similar difference in their 
pharmacological reactions. Another example of such difference is 
their behavior toward ammonia, which stimulates motor fibres hardly 
at ;ill but which stimulates sensory fibres more powerfully than 
either NaOH or KOH (Griltzner). 

Differences in the Pharmacological Reactions of Different Kinds of Nerve- 
fibres. — It might be possible to explain the difference in the reactions of these 
two types of fibres by assuming that a different degree of susceptibility to stimu- 
lation is a characteristic of their respective terminal organs, as a consequence 
of which, that minimum stimulation of the sensory fibres which would be sufficient 
to produce an effect in the central reflex mechanism, would be greater than that 
necessary to cause an effective stimulus to pass down the motor nerves to their 
terminal organs. More briefly expressed, we might assume a higher threshold 
value for stimulation of sensory nerves than for that of motor nerves. However, 
Dixon has shown that cocaine exerts a selective action on the fibres of the vagus 
also, abolishing the conductivity of the centrifugal cardio-inhibitory fibres and 
leaving unaffected the centripetal fibres connected with the respiratory and vaso- 
motor centres. Moreover, the centrifugal vasodilator fibres are more rapidly 
depressed by cocaine than are the vasoconstrictors. 

A difference in the reaction of the different types of fibres must, therefore, 
be conceded. Moreover, the greater susceptibility to cocaine manifested by the 
sensory fibres is only the maximal expression of a general law, for these two kinds 
of fibres exhibit a similar behavior toward the general anaesthetics (Pereles u. 
Sachs, Joteyko 11. Stefanowska) and also toward aconitine (Dixon). As a 
matter of fact, the same law holds good for the behavior toward drugs of the 
sensory and motor elements of the cord and brain, for ether, chloroform, etc., 
paralyze the sensory side of the spinal reflex arc and the sensory portion of 
the cerebrum before the motor excitability disappears (see p. 57 ff). It appears, 
therefore, that all sensory nervous elements are, as a rule, more readily depressed 
by chemical reagents than are the motor elements. 

Action on Other Tissues. — Although, as shown above, cocaine 
electively poisons the sensory nerve-endings and fibres, it never per- 
manently damages the other tissue cells unless too concentrated solu- 
tions are applied.* Other local anaesthetics closely related to cocaine, 
such as members of the orthoform group and stovaine, are not so free 
from such side actions. 

Actions on the Vessels. — These are the only organs besides the 
nerves which are markedly affected by the local action of cocaine. 
They are strongly constricted, and thus the blood supply at the point 
of application is markedly diminished. Under its influence hyperaemic 
and swollen mucous membranes become pale and the swelling dimin- 
ishes or disappears. This vasoconstricting action of cocaine is often 
of great value, as for example by rendering sinuses and cavities lined 
with mucous membrane (such for example as the nares) more accessible 

* [The cornea is especially likely to be damaged by too concentrated solu- 
tions. — Te.] 



COCAINE 125 

for surgical procedures. The anaemia also reinforces the anaesthetizing 
action of cocaine by retarding its absorption from the tissues into the 
blood, and thus keeping it for a longer time at the point of application. 
The great influence on the induction of local anaesthesia which is 
exerted by variations in the blood supply of the tissues is well shown 
by the fact that inflammatory hyperaemia of the eye renders its anaes- 
thetization by cocaine much more difficult, and may in fact entirely 
prevent it. On this account, the addition of epinephrin to the cocaine 
solutions often greatly augments the local anaesthetic action. A num- 
ber of the substitutes for cocaine do not possess this vasoconstricting 
power, while some of them directly counteract the vasoconstricting 
action of epinephrin. Cocaine's superiority in this particular over 
many of its substitutes is a point of much practical importance. 

Systemic Action. — In systemic poisoning by cocaine the depression 
of the sensory nerve-endings is not observed. It cannot, therefore, be 
considered as comparable to a drug possessing a "curare action" on 
the sensory nerve-endings, for, when equally distributed throughout 
the body by the blood, these nerve-endings are not the first elements to 
be affected, but, on the contrary, the central nervous system is the 
first organ to be affected. Only by the local application, which brings 
the cocaine in relatively high concentration in direct contact with the 
sensory nerve-endings and trunks, is it possible safely to abolish the 
function of these nervous elements. The great susceptibility of the 
central nervous system is responsible for the toxic effects which are 
observed in case too large amounts of cocaine are applied and absorbed. 

The action on the central nervous system consists in a primary 
stimulation and a secondary depression of certain tracts, regions, and 
functions, while others are depressed from the start. In the higher 
laboratory animals, very small doses cause the appearance of 
symptoms of excitation of the cerebral cortex, great restlessness, hal- 
lucinations, and uncontrollable motor activity. In man also, larger 
but not too large doses (maximal dosage 0.05 gm. per dose, 0.15 gm. 
per diem) [few American authors would consider 0.05 gm. (= 5 / gr.) 
a permissible dose. — Tr.] cause confusion, tendency to laughing, etc., 
a cocaine "Rausch,"* and finally delirium. This stimulating effect 
on the cortex no doubt is one of the reasons why coca leaves are used 
in South America as a stimulant or means of enjoyment (Genussmit- 
tel), while the suppression of sensations of hunger, emphasized in all 
reports concerning 1 his custom of the South American natives, is doubt- 
less due to the blunting of the sensibility of the nerves of the stomach. 

Tin;i; \ i ■ i ; i tically cocaine has been administered internally to 
alleviate gastric pail) and to relieve nausea of gastric origin. In 
conditions of mental depression, and especially during the withdrawal 
of morphine, attempts have been m;id<» to utilize the power of stimu- 

Etauscli is the German equivalent of the slang term "jag." 



126 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

lating the cortex possessed by small closes of cocaine. It was, however, 
quickly apparent that the danger of habituation was equally as great 
with cocaine as with morphine, and perhaps greater, and that the 
therapeutic use of cocaine in such cases led to a cocaine habit. 

TOXICOLOGY 

Toxic Action in Animals. — in warm-blooded animals the first 
stage of poisoning by cocaine is characterized by restlessness, excite- 
ment, and motor activity, followed by clonic convulsions and uncon- 
sciousness. The pulse is accelerated (accelerator stimulation), the 
blood-pressure raised, the pupils dilated (stimulation of sympathetic 
nerve-endings), and the body temperature is increased. In dogs it 
may be shown that these convulsions are of cortical origin, for Fein- 
l>< rg and Blumenihal found that they did not occur after previous 
extirpation of the cortex, nor were they to be seen in new-born puppies 
in which the cortical tracts are unexcitable. The convulsive stage is 
followed by a paralytic stage, with deep coma, loss of sensibility and 
power of moving, disappearance of the reflexes, and finally by death 
due to paralysis of the respiratory centre [and also of the vasomotor 
centres. — Tr.]. 

The symptoms of poisoning in man vary with the dose and espe- 
cially with the rapidity of absorption. When very toxic doses are 
gradually absorbed, the poisoning is characterized by unconsciousness, 
convulsions, and dyspnoea. At the start the preponderance of exci- 
tation may cause maniacal behavior or epileptiform convulsions, with 
extreme pallor, dilated pupils, and exophthalmos. When large enough 
doses are very rapidly absorbed, as occurs when strong solutions 
are applied to eroded mucous membranes, the poisoning may develop 
with very few symptoms, the victims suddenly fainting and becoming 
extremely pale and, after convulsions lasting but a short time, dying 
within a few minutes. With rapid absorption, such as may occur after 
subcutaneous injection, as little as 0.05 gm. may cause serious poisoning. 

The insufficient recognition of the fact that the rapidity with which cocaine 
is ahsorhcd varies markedly according to the method of application and the 
condition of the mucous membranes has led to a belief that different individuals 
exhibit a very different susceptibility to this drug. Many cases of apparent 
idiosyncrasy Bhouldj however, be interpreted as due solely to especially rapid 
absorption,* as has been emphasized by Broun.* 

The treatment op acute cocaine poisoning is purely sympto- 
matic. While anaesthetics or narcotics may be employed to control 
the convulsions, it must not be forgotten that their administration 
augments the danger from the paralysis which develops at a later stage. 
With threatening cessation of respiration, artificial respiration should 
be instituted. It goes without saying that, whenever possible, the effort 

* See in this connection the relationship between the actions of cocaine and 
epinephrin, pp. 159, 575). 



COCAINE 127 

should be made to prevent the further absorption, of the poison. In 
a case where the drug has been injected into an extremity, this is best 
accomplished by checking the circulation here by a tight bandage, 
and after its introduction into any of the body cavities by washing 
them out in the endeavor to remove any portions not yet absorbed. 

Avoidance of Rapid Absorption. — The poisonous effects on the 
central nervous system occur only when the drug is present in the 
blood in a certain concentration, which need never be attained when 
the drug is administered for its local effects, if, by use of proper 
methods, the drug is so administered as to permit a gradual, and to 
prevent a too rapid, absorption. Under these conditions such portions 
of the drug as enter the circulation are excreted, and, what is still 
more important, that portion which remains for a sufficient time in 
contact with the tissues is destroyed or altered by them. 

Distoxicatiox. — The rabbit after receiving a poisonous dose of cocaine 
excretes no unaltered cocaine, while the dog excretes only 5 per cent, of the 
amount administered {~\Yiechowski) . Anything which causes a retardation of 
the absorption and thus secures for the organs time to distoxicate the amounts 
gradually absorbed is, therefore, of the greatest service in lessening the danger of 
poisoning. This has been demonstrated by Kohlhardt, Klapp, and Kleine, who 
injected ordinarily lethal doses of cocaine into the leg of a rabbit after pre- 
viously tightly applying a rubber tube about the extremity. Under these con- 
ditions, the longer the constriction was maintained the more mild was the course 
of the poisoning. In an entirely similar manner, otherwise fatal doses of cocaine 
may be injected without danger if the paths of absorption are closed by adding 
to the solution epinephrin, our most powerful vasoconstricting agent. In such 
case the cocaine leaves the tissues very slowly, as they have thus been rendered 
nearly bloodless, and enters the circulation only gradually. 

PRINCIPLES GOVERNING THE ADMINISTRATION OF COCAINE 

So long as the entrance into the blood of cocaine and its distoxi- 
cation keep pace with each other, relatively large amounts may be 
administered. If this be borne in mind, the theoretical basis for the 
different methods of administration is readily arrived at. The indi- 
cation is to apply the cocaine in sufficiently concentrated form to the 
peripheral nervous elements which are to be anaesthetized, and to keep 
it there long enough to prevent its too rapid absorption. This indi- 
<-,il ion is met mainly in two ways. First, by using the weakest solution 
which will produce a complete anaesthesia and augmenting its effect by 
lirin.Lriiig it in intimate contact with the nerve-endings and prolonging 
the period of its eontacl with them. These are essentially the prin- 
ciples involved in infiltration anaesthesia. The second method consists 
in using relatively high concentrations but limiting their action to the 
neighborhood of the nerve-trunks. With both methods the addition 
of epinephrin to the cocaine solutions diminishes the danger of sys- 
temic poisoning. 

1. Surface ANESTHESIA of the mucous membranes, wounds, etc., 
may he secured hy simply dropping on them solutions of cocaine or by 
applying the solutions with a brush or in cotton tampons and by 



128 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

similar simple methods. Anaesthesia thus induced is a terminal one, — 
i.e., one affecting only the terminal sensory nervous elements. When 
the solution can remain for only a short time in contact with the mucous 
membrane, — as, for example, when it is used for operation on the nose 
or throat, — as a rule, concentrated solutions, 10-20 per cent. [ ! ! Tb.],* 
must be applied. On the other hand, for superficial anaesthesia of the 
cornea a 2 per cent, solution is sufficient. As a solution injected into 
the bladder or urethra may remain longer in contact with the mucous 
membranes, 2-5 per cent, solutions are strong enough. The danger of 
systemic poisoning increases with the extent of the mucous membrane 
to which the solution is applied and with its power of absorption, and 
it should be remembered that this danger is the greatest when the 
mucous membrane is hyperaemic and especially when it is ulcerated. 
The addition of epinephrin to the solutions retards the absorption 
without lessening the depth or duration of the anaesthesia. 

In the Eye. — The tissues of the eye present such favorable con- 
ditions for the absorption of the anaesthetic that in two minutes 
after dropping in a little 2 per cent, solution complete insensi- 
tiveness is secured. Accompanying this are dilation of the pupil, 
protrusion of the eye, and widening of the palpebral fissure, all due 
to stimulation of the sympathetic. 

2. Hypodermic and Endermic Injections. — Originally 1 to 5 per 
cent, solutions were used for subcutaneous injections. Here the anaes- 
thesia is in part a terminal one and in part dependent on blocking 
of the conducting fibres. As cocaine is very rapidly absorbed from 
the subcutaneous tissues when its absorption is not artificially pre- 
vented, — as, for example, by an Esmarch bandage, — the use of such 
concentrated solutions is almost more dangerous than a chloroform 
anaesthesia. By using weaker solutions the danger from absorption 
may be lessened without interfering with the induction of complete 
local anaesthesia. 

Infiltration anaesthesia (Schleich) consists in infiltrating the 
skin over the region to be incised by means of endermal injections 
of cocaine solutions and then infiltrating the lower layers one after 
another. When the solution is thus brought into such intimate contact 
with the nerve-endings in the field of operation, a satisfactory anaes- 
thesia may be obtained by the use of very dilute solutions which are 
just strong enough to anaesthetize the nerve-endings, but the anaesthesia 
does not extend beyond the infiltrated area, for the dilute cocaine 
solution is efficient only at the point of application. Schleich recom- 
mended adding to the 0.1-0.2 per cent, cocaine solution only 0.2 per 
cent, of NaCl, as he believed that the hypotonicity of the solution, by 
causing a certain amount of "imbibition "anaesthesia (seep. 120), would 
increase the effect of the cocaine. At present the general preference is 

* [The careless use of such strong solutions may readily result in serious 
poisoning; 5TT1. of 20 per cent. sol. = 1 gr. — Tr.] 



COCAINE 129 

for the addition of 0.8 per cent. NaCl, as advised by Braun and 
Heinze, with the object of avoiding any damage to the tissues. Schleich's 
solutions contain morphine, but, as morphine has no local anaesthetic 
powers, the morphine may just as well [or better. — Tr.] be injected 
before or after the operation. 

Nerve Blocking. — Infiltration anaesthesia, however, is not appli- 
cable in all conditions or situations. For example, the pain caused 
by the numerous injections into inflamed tissues prevents its use under 
such conditions. When such is the case, the method of nerve blocking 
(conduction anaesthesia) is indicated, a method in which the danger 
of systemic poisoning from absorption is avoided in a different fashion. 
The injection of a small quantity of a solution of cocaine under the 
sheath of a nerve and between the nerve-fibres causes an immediate 
interruption of their conductivity. As, however, endoneural injection 
usually succeeds only when the nerve-trunk has first been exposed, as a 
rule recourse is had to perineural injection, which necessarily demands 
a stronger solution than the endoneural application. 

This nerve blocking, which causes a regional anaesthesia, is useful 
for many and various operative procedures, and is especially adapted 
to dentistry (Peckert). It is also particularly adapted to the anes- 
thetization of fingers and toes, where its effects should be augmented 
by the use of epinephrin or tight bandaging. Even major operations, 
for example, those involving the breast or the thorax, where the inter- 
costal nerves may be "blocked," may be performed painlessly with 
the aid of perineural injections (Hirschl). 

Circular ancesthesia according to Hackenbruch's method is a third 
method, occupying an intermediate position between infiltration anaes- 
thesia and regional anaesthesia. Here the tissues surrounding the field 
of operation are injected in a continuous irregular circle in such 
fashion as to block all the sensory nerves supplying the part. 

3. Spinal Anaesthesia. — Here the cocaine acts on the sheathless 
nerve-roots as they emerge from the cord and on the nerve-trunks lying 
in the lumbar dural sac, which are bathed by the anaesthetizing solu- 
tion, a nerve blocking resulting. 

Medicine owes the introduction of this method to Bier, of Berlin. 
The injection in man of 0.005-0.03 gm. of cocaine into the lumbar 
subdural space is quickly followed by paraesthesia, and soon after- 
ward (in 5 to 30 minutes) by abolition of the pain sense in the lower 
portion of the body, the sensation of touch, the power of motion, and 
the reflexes still persisting. With further development of the action 
thf excitability of the other sensory paths is abolished, and after 
still larger doses there occur motor weakness and paralysis of the 
lower half of the body. Here the cocaine clearly acts more strongly 
on the sensory than on the motor elements. The undesirable and often 
dangerous side actions, which have not infrequently been observed 
in lumbar anaesthesia, are all probably due to a spreading of the 
9 



130 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

cocaine inside the dura up along the cord until it can act directly on 
the higher vital centres. For this reason, it is especially important 
in lumbar anaesthesia that we should be able to substitute for cocaine 
some less toxic substance. 

By a new method, sacral anesthesia (Stoeckel, Lumen, Schlimpert), in 
which the cocaine solution is injected into the sacral canal, the attempt has been 
made to block the spinal nerve-roots after they emerge from the dura. This- 
method is employed chiefly by gynaecologists for special indications. As is self- 
evident, it is necessary to use stronger solutions here than when they are injected 
intradurallv. otherwise the well-developed nerve-sheaths will not be penetrated 
by the cocaine in effective amounts.* On the other hand, as the cord is protected 
from the drug [and as the cocaine cannot pass up alongside of the cord to the 
vital centres. — Tk.]. the side actions are much less pronounced (Schlimpert). 

BIBLIOGRAPHY 

Alms: Dubois' Arch., 1886. 

v. Anrep: Pfluger's Arch., 1880, vol. 21, p. 38. 

Bier: Zeitschrift f. Chimrgie, 1899, vol. 51, p. 3G1. 

1 Braun: Arch. f. klin. Chir., 1898, vol. 57. 

2 Braun : Die Lokalaniisthesie, Leipzig, 1905, p. 49. 

3 Braun : Die Lokalaniisthesie, Leipzig, 1905, p. 94. 
Dixon: Journal of Physiology, 1905, vol. 32, p. 87. 

Ehrlich u. Einhorn: Ber. d. Deutsch. Chem. Gesellsch., 1894, p. 1870. 

Feinberg u. Blumenthal: Berl. klin. Woch., 1887, p. 1GG. 

Filehne: Berl. klin. Woch., 1887, p. 107. 

Gradenwitz: Inaug.-Diss., Breslau, 1898. 

Gros: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 80; Miinchn. med. Woch., 

1910, No. 39. 
Grutzner: Pfluger's Arch., 1894, vol. 58. 
Eeinze: Virchow's Arch., 1898, vol. 153. 
Hirshl: Miinchn. med. Woch., 1911, No. 10. 

Joteyko u. Stefanowska: Ann. Soc. roy. des sciences med., Bruxelle, vol. 10, 1901. 
Klapp: Verhandl. d. Deutsch. Chirurgenkongr., 1904, p. 260. 
Kleine: Zeitschr. f. Hygiene, 1901, p. 36. 
Kochs: Zentralblatt f. klin. Medizin, 1SS6, vol. 7, p. 793. 
Kohlhardt: Verhandl. des Deutsch. Chirurgenkongresses, 1901, p. 644. 
Lawen: Miinchn. med. Woch., 1910, No. 39. 

Liebreich: Verhandl. d. 7. Kongr. f. inn. Medizin, 1888, p. 245. 
Loewy u. Miiller: Miinchn. med. Woch., 1903, No. 15. 
Moreno y Mays: These de Paris, 1868. 
Peckert: Die zahnarztliche Lokalaniistesie, etc., Habilitationsschr., Heidelberg, 

1905. 
Pereles u. Sachs: Pfluger's Arch., 1882, vol. 52. 
Poulsson: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 301. 
Bantesson: Festschrift fiir Hammarsten, 1906. 
Schleich: Verhandl. d. Deutsch. Chirurgenkongr., 1892; Schmerzlose Opera- 

tiohen, Berlin, 1894, p. 121. 
Schlimpert u. Schneider: Miinchn. med. Woch., 1910, No. 49. 
Schlimpert: Zentralblatt f. Gynakologie, 1911, No. 12. 
Stoeckel: Zentralbl. f. Gyn., 1909, No. 1. 
Tumass: Arch. f. exp. Path. u. Pharm., 1886, vol. 22, p. 107. 
Wiechowski : Arch. f. exp. Path. u. Pharm., 1901, vol. 46, p. 155. 
Wi'ihlcr: Annalen d. Chemie u. Pharmazie, 1860, vol. 114, p. 216. 
Zwardemaker, cited from Braun: Die Lokalaniisthesie, p. 8(i. 

* Novocfiine bicarbonate, on account of its rapid diffusibility, is especially 
adapted for this method (see p. 122). 



SUBSTITUTES FOR COCAINE 



131 



SUBSTITUTES TOR COCAINE 
Starting from a knowledge of the constitution of cocaine, by 
systematic study of the question as to which atom groups cause the 
action on the sensory nerves and how the reciprocal relation of these 
groups affects this action, it has been possible to synthetize a consider- 
able number of substitutes for cocaine. These substitutes, generally 
speaking, possess the advantage of being, when used in equal con- 
centration, cheaper, less toxic, more stable in solution, and of being 
more readily sterilized, but they are also less powerful ansesthetics 
than cocaine. They can often replace cocaine in practice or be used 
as adjuvants to it. 

CONSTITUTION OF COCAINE 

Strong alkalies decompose cocaine into the base ecgonine, methyl alcohol, 
and benzoic acid. 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



-CH- 



N(CH 3 ) 



-CH- 



COOH 

> 

-CH 2 






-CH- 



OC 



Ecgonine. 

COOCH3 

H 

O • COC 6 H 5 



n(ch 3 ) y 

-CH CH 2 



Benzoyl-methyI-ecgonine = Cocaine. 

CH CH 2 



r(CH,) 



if 



'O.COCeHs 



-CH- 



-CH 2 



Benzoyl-tropine. 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



H 2 C- 



-CH- 



C< 



COOCH, 



N(CH 3 ; 



-CH- 



-CH 2 

Methyl-ecgonine. 

CH CH 2 



N(CH 3 ) 



OH 



; / H 

\)H 



-CH- 



-CH 2 



Tropine. 



-CH~ 

I 
CH 2 

I 
N(CH 3 

-ck- 



-C< 



H 

O • COC 6 H s 



CH 2 



Benzoyl-pseudotropine = Tropacocaine. 



Methyl-eogoninc is inactive, being rendered active only when a benzoyl 
radical is introduced (Filehne, Ehrlich u. Einhom) . According to the former 
author, not all acid radicals produce this effect, for the substitution for the 
benzoyl radical of other aromatic acid radicals weakens the anajsthetic activity, 
and it is completely abolished by the substitution of aliphatic acid radicals. 
Furthermore the discovery, in Javanese coca leaves, of tbopacocaine, the basic 
nucleus of which, pseudotropine, also contains the benzoyl group, lias emphasized 
the importance of this group for the specific activity of these substances. As a 
matter of fact, Filehne was able to demonstrate the local anaesthetic powers of 
other benzoylated alkaloids, — e.g., benzoyl-tropine. From these facts it may be 
concluded that the specific local anaesthetic action is due to the combination 



132 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

of certain nitrogenous basic substances with the benzoyl radical. If the basic 
complex contains a COOH group, as is the case with eegonine, its acid nature 
must be overcome by esterfication with a methyl or ethyl radical or with some 
other aliphatic radical (Poulsson). 

Einhorn's SV investigations have shown that local anaesthetic power is 
a common property of all basic esters of benzoic acid, although it varies in 
individual cases to a marked degree. While many other aromatic esters also 
possess this power, a practical importance is possessed only by those compounds 
which exert a sufficient degree of local anaesthetizing action without damaging 
the tissues. In addition a sufficient solubility in water is essential for their 
subcutaneous and intradural administration. 

Orthoform Series. — Einhom and Heinz, by investigating the 
action of very simply constituted derivatives of benzoic acid, 
C 6 H 5 .COOH, and of oxybenzoic acid, C 6 H 4 OHCOOH, in which the 
very complicated nitrogenous basic radical of cocaine, tropacocaine, 
etc., was replaced by the amido group, obtained the various orthoforms. 
These are substances which are but slightly soluble in water and which 
are much used as analgetic dusting powders. 



NH 2 



OH 



HC 

HC. /CH 
C 
COOCH3 

Benzoic acid, methyl ester. 



CH 



CH 



OH • C 



HC 



C 

I 
COOCH3 

Para-amido-meta-oxy- 
benzoic acid methyl eater, 
Orthoform. 



NH 2 • C 



HC 



CH 



;CH 



COOCH3 

Meta-amido-para-oxy- 
benzoic acid methyl ester, 
Orthoform, new. 



Other numbers of this group are the more soluble nirvanin and 



an^sthesin (Dunbar, v. Noorden, Spiess) 



NH* 





HC 



HC 



CH 



CH 



N< 



COCH 2 -N(C 2 H 6 ) 2 , HC1 



C 
Hc/^CH 



OH • C v , CH 



X)OC,H s 



p-amidobenzoic acid methyl 
ester, Ansesthesin. 



c 
I 
COOCH3 

The hydrochloride of diethyl p-amido-o-oxy- 
benzoic acid methyl ester, Nirvanin. 



Novocaine. — Another group of active local anaesthetics have been 
discovered in benzoyl derivatives of the amino-alcohols which were 
first investigated by Einhorn. Among these is novocaine (Einhom*), 



SUBSTITUTES FOR COCAINE 



133 



which appears to be the best of the cocaine substitutes (Biberfeld, 
H. Braun). 

NH 3 

I 
C 



HC 



HC 



CH 



CH 



C 
I 
COO(CH 2 CH 2 N[C 2 H 6 ] 2 )HCl 

The hydrochloride of p-amido-benzoyl-diethyl- 
amidoethanol, Novocaine. 

Stovaine (Fourneau), alypin (Impens), and eucaine also belong 
to this series. The lactate of beta-eucaine is sufficiently soluble and is 
much used. 



HC 



HC 



CH 



/'CH 

C CH 3 

COO • C- 

C^Hs 



CH 2 -N(CH 3 ) 2 -HC1 



The hydrochloride of dimethylamidoben- 
zoylpentanol, Stovaine. 



HC 



CH 



CH 



C CH 2 -N(CH 3 ) 2 
I I 

COO-C-CH 2 -N(CH 3 ) 2 

C 2 H5 



HC1 



The hydrochloride of tetramethyldiamino- 
benzoylpentanol, Alypin. 



H 
C 

HC /^ CI 



HC\ /CH 



f cH^c<gg; 

coo ■ C/ ^>NH 

CH 2 CH • CH 3 

Trimcthylbenzoyl-oxypiptTidinc = Hue: 



< < >.M pa i;.\ri \ i: values 



OF THE SUBSTITUTES 
THEIR USES 



KOI! (OCA I XI-: AN' I) 



The synthetic cocaine substitutes may ho slcrili,:< <l. are fairly 
stable in solution, and are all less toxic to the central nervous system 
than cocaine. According to Brocqu, tropacocaine and novocaine are 



134 PHARMACOLOGY OF SENSORY NERVE-ENDINGS 

only half as toxic as cocaine and beta-eucaine is even less so, but their 
anaesthetic action is also weaker. It would appear tJiat the toxicity 
for the central nervous system runs parallel with the ancssthetic action 
on the nerve-endings. 

Tropacocaine (Chadbourne) , derived from the Javanese coca 
leaves, while less toxic is also much more evanescent in its local anaes- 
thetic action, but may be used if the circulation is interrupted by a 
tight bandage or by pronounced cooling. On account of its relatively 
slight toxicity, it has recently been used in preference to cocaine for 
spinal anaesthesia. In the eye it causes slight mydriasis and no 
irritation. 

Beta-eucaine (Vinci) is also much less toxic than cocaine, its toxic 
dose being three times as large. It possesses the disadvantages of 
being somewhat irritant and of causing local hypersemia. 

Stovaine is much used for intradural anaesthesia, especially in 
France (Challamel), but it is not altogether harmless to the tissues, 
for, in the presence of alkaline carbonates, the insoluble carbonate of 
dimethylamidobenzoylpentanol is precipitated. The carbonate of its 
homologue, alypin, being soluble, this drug does not cause local irri- 
tation (Braun 2 , Lawen 2 ). 

While the anaesthesia produced by novocaine is more evanescent 
than that produced by cocaine, it apparently does not damage the 
tissues and is considered by many to be the best of the cocaine substi- 
tute (Brocqu, Gros, Braun, 1 Heinecke, and Lawen 1 ). 

Ortho-form and others of this group are not substitutes for cocaine, 
but are rather to be considered as complementary substances (Spiess). 
Most of them being rather insoluble, they are not adapted for subcu- 
taneous use, and even when soluble, as is the case for example with 
nirvanin, their anaesthetic action is too weak for them to be of value 
when thus administered. On the other hand, orthof orm is employed as 
a rather insoluble dusting powder for wounds and iilcers. As it pene- 
trates the skin and mucous membranes with difficulty, it relieves pain 
only when brought in contact with exposed nerve-endings, in which 
case its action is rather prolonged. It should, however, be used cau- 
tiously, for it may produce other undesirable local effects, such as 
oedema, eczema, and gangrene, especially when used in the treatment 
of ulcers of the leg. It also transforms oxyhaemoglobin into methaemo- 
globin, even in a dilution of 0.02 per cent. It should, therefore, not 
be used in the treatment of open wounds or of gastric or intestinal 
ulcers, nor should it be injected into the tissues (Frohlich). 

An^esthesin is employed in the same way as orthoform, and 
causes a prolonged local anaesthesia, apparently without producing 
the harmful effects seen with orthoform. In the form of its p-phenol- 
sulphonate, subcutin, it may be administered subcutaneously, but is 
very irritant locally (Braun 3 ). 

The differences in action between cocaine and its above-mentioned 



SUBSTITUTES FOR COCAINE 135 

substitutes, many of which are still in the experimental stage, are to 
some degree qualitative as well as quantitative, for when applied to 
mixed nerves all of them do not appear to exert so elective an effect 
on the sensory nerves as does cocaine. Stovaine, for example, in dilute 
solution strongly depresses the motor nerve-endings (Santesson) . In 
judging of their value, the most important points are the rapidity 
with which recovery of normal function occurs after their employ- 
ment and the extent to which they cause permanent damage to the 
nerves. In these respects also cocaine apparently is superior to all 
its substitutes with the exception of novocaine (Lawen 1 ). In addi- 
tion the value of many of these drugs is impaired by the fact that they 
(e.g., eucaine and tropacocaine) dilate the vessels, and thus lessen or 
prevent (Lawen 2 } 3 ) the favorable effect of the addition of epinephrin. 

BIBLIOGRAPHY 

Biberfeld: Med. Klinik, 1905, No. 48. 

1 Braun, H. : Deutsche med. Woch., 1905, No. 42. 

2 Braun H. : Lokalanasthesie, p. 132. 

3 Braun H. : Lokalanasthesie, p. 130. 
Broequ: British Med. Journal, March, 1909. 
Chadbourne: Therapeut. Monatsh., 1892, p. 471. 

Challamel, A.: Receuil des principaux Memoires cone, la Stovaine, Paris, 1904. 

Dunbar: Deutsch. med. Woch., 1902, No. 20. 

tinhorn: Liebig's Annalen, 1900, vol. 311. 

2 Einhorn: Liebig's Annalen, 1902, vol. 325. 

■Einhorn: Liebig's Annalen, 1908, vol. 359. 

4 Einhorn: Ber. d. Deutsch. Chem. Gesellsch., 1894, vol. 27, p. 1873. 

Ehrlich u. Einhorn: Ber. d. Deutsch. Chem. Gesellsch., 1894, vol. 27, p. 1870. 

Einhorn u. Heinz: Miinchn. med. Woch., 1897, No. 34. 

Filehne: Berl. klin. Woch., 1887, p. 107. 

Fourneau: Compt. rend, de 1'Acad. des sciences, Paris, Feb., 1904. 

l'ruhlkh. A.: Wiener klin. Woch., 1909, p. 1805. 

Gros: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 80. 

Heinecke u. Liiwen: Deutsche Zeitschr. f. Chir., vol. 80, p. 186. 

Impens: Pfliiger's Arch., 1905, vol. 110, p. 21. 

1 Lawen: Beitr. z. klin. Chirurgie, 1906, vol. 50, p. 621. 

8 Liiwen: Arch. f. exp. Path. u. Pharm., 1904, vol. 51, p. 415. 

3 Liiwen: Deutsche Zeitschr. f. Chir., 1904, vol. 74, p. 163. 

v. Noorden: Berl. klin. Woch., 1902, No. 17. 

Poulsson: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 301. 

Santesson: Festschr. f. Hammarsten, 1906. 

Spiess: Miinchn. med. Woch., 1902, No. 39. 

Stoeckel: Zentralblatt f. Gvniikologio, 1909, No. 1. 

Vinci: Vircliow's Arch., 1897, vol. 149, p. 217. 



CHAPTER IV 

PHARMACOLOGY OF THE VEGETATIVE NERVOUS 
SYSTEM 

Thus far we have discussed only the so-called animal nervous 
system, and the manner in which pharmacological agents may in- 
fluence the functions of its various parts, the sensory nerve-endings, 
the cerebral, medullary, and spinal centres, and the efferent nerves 
which carry motor impulses to the voluntary striped muscles. We 
have taken these up in a particular order, believing that by so doing 
we have laid the foundation for a clearer understanding of the manner 
in which pharmacological actions should be analyzed. 

THE VEGETATIVE NERVOUS SYSTEM 
In opposition to the animal nervous system, which is under the 
control of the will, stands the so-called vegetative system, the efferent 
nerves of which supply those organs whose functions are not under the 
control of the will. These are the glands and the organs containing 
smooth muscles, such as the viscera, the vessels, the smooth musculature 
of the skin, the iris, etc. Physiologically similar to these organs with 
smooth muscle are certain striated muscles, — viz., those of the heart, 
the oesophagus, and the penis, and in certain animals the iris, which, 
in the birds for example, is composed of striped muscle. The charac- 
teristic quality of the innervation of all these tissues is due to the fact 
that their functions, although they may be influenced through the 
central nervous system, are able to continue independently of it. 
The nervous system which innervates them possesses a certain, although 
limited, independence of the central nervous system, and has conse- 
quently been named by Langley the autonomic nervous system. 
However, we shall retain the name, vegetative nervous system, and use 
the term autonomic (parasympathetic) only for that portion of the 
vegetative system which does not arise from the sympathetic trunk.* 
The efferent fibres of the vegetative nervous system reach their 
terminal organs — the muscles of the circulatory, digestive, and sexual 
organs and the glands, etc. — through nerves which emerge from 
peripheral nerve-ganglia. While vegetative nerve-fibres originate in 
the central nervous system, it is characteristic of the vegetative nerves 
that they never pass directly from the central nervous system to the 
periphery, without first connecting, during some portion of their 
course, with ganglion-cells. 

Sympathetic Nervous System. — Differing both anatomically and 

* [For this system Langley has more recently suggested the name parasympa- 
thetic, and this term will also be used in this work. — Tb.] 
136 



ANATOMY AND PHYSIOLOGY 137 

embryologically, as well as physiologically and pharmacologically, from 
the other vegetative fibres is the group of sympathetic fibres, which 
emerge from the middle portion of the spinal cord in the thoracic and 
the first 4 or 5 lumbar nerves and pass through the white rami com- 
municantes to the sympathetic trunk and to the superior and inferior 
cervical and the stellate ganglia, from which ganglia they join the 
spinal nerves through the gray rami communicant es. These sympathetic 
nerves supply the vessels, glands, and smooth-muscled organs through- 
out the body and form a homogeneous portion of the vegetative nervous 
system.* In the accompanying diagram (p. 139) these nerves are 
colored red. 

Autonomic or Parasympathetic System. — However, almost all 
these organs, as indicated by the nerves colored blue in the diagram, 
also receive another sort of vegetative nerves, some of which arise 
from the brain and medulla, and others from the sacral cord, and 
which are called by us the cranial, and the sacral autonomic (para- 
sympathetic) nerves. Autonomic nerves also arise from the midbrain, 
which run in the oculomotorius to the ciliary ganglion, from which 
they pass as the short ciliary nerves to the sphincter of the iris and the 
ciliary muscle. 

In the chorda tympani are secretory fibres for the salivary glands, 
and vasodilator fibres for the oral cavity, which are autonomic 
nerves arising from the medulla. The facial and glossopharyngeal 
nerves also contain secretory and vasodilator fibres, which pass into 
the trigeminus and supply the oral, nasal, and pharyngeal mucous 
membranes. Finally, autonomic fibres emerge from the medulla oblon- 
gata and run in the vagus to the viscera. These are the cardio- 
inhibitory fibres, constrictors for the bronchial muscles, motor fibres 
for the oesophagus, stomach, and intestine, and secretory fibres for the 
stomach and the pancreas. This autonomic system may be named the 
eranial-bulbar or, briefly, the cranial autonomic system. Its influence 
is most powerful at the oral end of the alimentary canal and in the 
neighboring structures of the head, and from there down diminishes 
in extent and intensity. Near the anal end of the alimentary canal it 
is replaced by the sacral actonomic system, the fibres of which pass 
from the cord in the first sacral nerve, and, as the nervus pelvicus, 
supply the lower portion of the alimentary canal — the descending 
colon, rectum, and anus — as well as the bladder and genital organs. 

A third nervous mechanism controlling the automatic movements 
of the hollow viscera, such as the intestine, has received from Lanfjlrij 

* As a result of the labors of Qa&kell, Langley, and others, our knowledge 
of the structure and function of tli<' sympathetic and of the other autonomic 
systems has undergone a complete transformation in recent years. The following 
description is based on the views developed by Langley, which may lie found as 
described by him in Bchaefer's text-book on physiology, 1000, vol. 2, p. 616, and 
in Asher-Spiro's Ergebn. d. IMiysioIogie, 1903, vol. 2, p. 808. The nomenclature 
followed, however, is the one indicated above. 



138 PHARMACOLOGY: VEGETATIVE NERVOUS SYSTEM 

the name of the ' ' enteric system. ' ' These are peripheral automatic 
centres, which, however, receive impulses from the central nervous 
system through autonomic and sympathetic fibres. 

All the sympathetic nerves form a physiological unit, and every- 
where their nerve-endings exhibit one common pharmacological reac- 
tion (to epinephrine. According to Langley, on the other hand, the 
cranial and the sacral autonomic systems belong together in a physio- 
logical sense. This physiological relationship is most strongly demon- 
strated by their similar reaction to a number of drugs and poisons, to 
which we will later turn our attention. Pharmacologically the cranial 
and sacral autonomic systems exhibit a distinct contrast to the sympa- 
thetic system, just as they do in respect to their functions, and this too 
in spite of the fact that both types of vegetative nerves appear to be 
essentially similar in structure. 

However, all the vegetative nerves, in accordance with this similar 
structure, possess one pharmacological reaction in common, the dis- 
covery of which was a decisive step toward the recognition of their 
true nature. This is their reaction to nicotine, which exerts an elective 
action on one particular portion of all vegetative nerves. In accord- 
ance with the general scheme of their arrangement, the vegetative 
nerve-fibres, unlike those of the animal system, never pass directly 
from the central nervous system to their terminal organs, but, after 
leaving the gray matter of the central nervous system, pass into ganglia 
in which the central fibres terminate, coming at this point into close 
relationship with the ganglion-cells, from which new nerve-fibres then 
pass down to the terminal organs. These separate fibres are conse- 
quently named the pre-ganglionic and the post-ganglionic fibres. The 
course of the vegetative nerves is always interrupted in a ganglion, 
and in the whole course of the nerve only in a single ganglion, where 
there is, as it were, a switching of the impulse from the pre-ganglionic 
to the post-ganglionic fibres. This interruption of the impulse may 
occur in the first ganglion through which the nerve passes, — for 
example, in one of the vertebral ganglia, which, like the spinal ganglia, 
are segmental ly arranged in the sympathetic trunk. Other vegetative 
fibres, however, pass through a first and often a second ganglion, which 
may be interposed in their path, without branching in them, and 
terminate only in more peripherally situated prevertebral ganglia, — 
for example, the nerve fibres of the splanchnicus terminate in the 
solar plexus and those of the pelvic nerve in the hypogastric plexus, 
while others may terminate in still more peripherally lying ganglia, 
which are situated directly in the terminal organs. 

Tlic vertebral ganglia, with the exception of the superior and inferior cer- 
vical ganglia, supply the vegetative organs of the skin and the trunk and extremi- 
ties, which include the glands, the vessels, and the smooth muscles of the skin, 
while the prevertehral ganglia supply exclusively the viscera. The stellate and 
the superior cervical ganglion, which may be looked upon as resulting from the 
fusion of vertebral and prevertebral ganglia, supply both viscera and skin. 



140 PHARMACOLOGY: VEGETATIVE NERVOUS SYSTEM 

Common Reaction to Nicotine. — Xo matter at what point the 
central fibres terminate and this switching occurs, and no matter what 
the function of the post-ganglionic fibres, whether motor, inhibitory, 
or secretory, nicotine always, after a primary stimulation, causes a 
paralysis of this relay station, or ganglion. This is the general rule 
to which there are no exceptions, although the different ganglia exhibit 
a variable degree of susceptibility toward this poison and although 
greater differences are exhibited by different species of animals; for 
example, nicotine acts far less powerfully on these ganglia in the dog 
than in the cat or rat. 

Langley, by applying a dilute solution of 0.5 per cent, of nicotine to the 
separate exposed ganglia, produced a localized poisoning, and, using this method, 
was able to employ this drug as the means of determining whether an efferent 
vegetative nerve-fibre passed through the ganglion in question without joining 
it. or whether at the poisoned point the fibre terminated and entered into a 
physiological union with the ganglionic cells. If stimulation of the nerve at a 
point lying centrally to the ganglion still produced the same effect as before the 
application of the poison, it was clear that its nerve-fibres merely passed through 
the ganglion, but if such stimulation did not produce such effect, it was evident 
that the nerve-fibres in question terminated in this ganglion, and that the post- 
ganglionic fibres arose from it. By means of this method, Langley was able 
to demonstrate the interruption of numerous sympathetic and cranial and sacral 
autonomic nerves in their various vertebral and prevertebral ganglia. One 
example may serve to make this more readily understood. Stimulation of the 
cervical sympathetic below the stellate ganglion causes dilation of the pupil, 
widening of the palpebral fissure, and alteration of the calibre of the vessels 
and of the secretory functions of the cranial mucous membranes. After appli- 
cation of nicotine to this ganglion the same stimulation produces no vasoconstric- 
tion in the upper extremity, but still produces the same effects in the eye and in 
the cranial mucous membranes. From this it is evident that the vasomotor nerves 
of the upper extremity enter into some sort of a union with the ganglionic cells, 
while the nerve-fibres for the pupil and for the cranial mucous membranes pass 
through this ganglion and do not find their relay station until they reach the 
cervical ganglia. 

After the injection of nicotine into the circulation, stimulation of 
all pre-ganglionic fibres is ineffective, while stimulation of postgan- 
glionic fibres causes all the usual effects. This shows that the nerve- 
fibres and their peripheral nerve-endings remain excitable and that 
nicotine poisons only the relay stations in the ganglia. 

The Antagonistic Functions of the Sympathetic and Auto- 
nomic or Parasympathetic Systems. — The action of the nicotine is 
exerted on all the ganglia of the entire vegetative system, whether their 
fibres originate from the sympathetic or from the autonomic system, but 
otherwise these two groups of vegetative nerves in many respects 
exhibit an antagonistic physiological and pharmacological behavior. 
In this connection it is a fact of very great importance that most of 
our organs possess a double innervation, coming on the one hand from 
the sympathetic system and on the other from the cranial or 
sacral autonomic (parasympathetic) system, and that almost every- 
where, where organs are thus doubly innervated, this double inner- 



SYMPATHETIC NERVOUS SYSTEM 141 

vation is an antagonistic one, the stimulation of the sympathetic 
fibres causing the opposite effect from that produced by stimu- 
lating the fibres belonging to the autonomic system. For example, 
the splanchnicus, a sympathetic nerve, inhibits the movements 
of the intestine, while the parasympathetic fibres of the vagus and the 
sacral fibres of the pelvicus excite the motor activity of the upper 
and lowest portions of the intestines. This antagonism is also evi- 
denced by the following physiological facts: Thus, the dilator of the 
iris is innervated by the sympathetic, while the antagonistic sphincter 
of the iris is innervated by autonomic fibres in the oculomotorius, and 
the cardio-inhibitory fibres of the vagus are opposed by the sympathetic 
accelerans. In short, almost all organs for which a double inner- 
vation from both systems has been demonstrated are antagonistically 
influenced through these systems. There exists, however, a group of 
organs, — viz., the vessels and glands of the skin — which, so far as 
our present knowledge goes, appear to be innervated only by the 
sympathetic system. 

Epinephrin a Specific Poison for Sympathetic Nerve-endings. — 
The different physiological behavior of the two vegetative systems 
expresses itself also in their reaction to pharmacological agents, there 
being one group of drugs which act only on the sympathetic nerve- 
endings, and another which acts on all the various autonomic nerve- 
endings. Thus, epinephrin, the suprarenal hormone, excites all the 
nerve-endings which in the accompanying diagram are colored red, — 
that is, it always produces the same effects on the various organs as 
are produced by stimulation of their sympathetic nerve-fibres. Owing 
to this action on the sympathetic nerve-endings, epinephrin causes 
vasoconstriction in all vascular systems [except the pulmonary and 
coronary ? — Tr.], strengthening and acceleration of the heart-beat simi- 
lar to that caused by stimulation of the accelerans, dilatation of the 
pupil like that produced by stimulation of the cervical sympathetic, 
and secretion of the salivary glands in so far as these glands are ren- 
dered active by stimulation of their sympathetic nerves. 

Where, however, sympathetic fibres are inhibitory in their func- 
tions, — for example, in the stomach and intestine, or in the bladder, — 
epinephrin does not cause a stimulation, but, on the contrary, an inhibi- 
tion of their motor functions. Epinephrin always produces the same 
effect as the stimulation of the sympathetic nerve of any organ, a fact 
which is especially strikingly demonstrated in those organs in which 
stimulation of the sympathetic nerves causes in one species of animal 
contraction and in another relaxation, as is the case for example in 
the bladder (Elliot). It may, therefore, be stated that epinephrin 
produces excitation only on those vegetative nerve-endings which 
belong to the sympathetic system.* 

* With tlio Bingle exception of tlie Bweat-glands which renot to pharmaco 
logical agents as if aut< mically innervated. 



142 PHARMACOLOGY: VEGETATIVE NERVOUS SYSTEM 

In ergotoxix, a substance present in ergot, Dale has discovered another 
toxic substance which also exhibits a limited elective affinity for certain of the 
sympathetic nerve-endings, for it poisons only the nerve-endings of those fibres 
the stimulation of which causes motor activity, and produces no effect on those 
causing inhibition. After large doses of ergotoxin a stimulation of vasocon- 
strictor nerves no longer causes vasoconstriction, the accelerans loses its influence, 
and so forth, while the inhibitory influence of the splanchnicus on the intestine 
or of the sympathetic nerves on the bladder, in those animals in which they inhibit 
this organ, remains unaffected. 

Specific Poisons for Autonomic or Parasympathetic Nerves. — 
While epinephrin produces no effect on the cranial and sacral autono- 
mic nerve-endings, there is another group of drugs which act particu- 
larly on these organs, leaving the sympathetic nervous system, with one 
exception, entirely unaffected. The chief representatives of this group 
are atropine on the one hand and muscarine, pilocarpine, physostig- 
mine, and choline on the other. Of these muscarine stimulates and 
atropin paralyzes the nerve-endings of the autonomic fibres which in the 
diagram are colored blue. This antagonism holds good right down the 
line, muscarine causing miosis, and atropine, by preventing the action 
of the autonomic oculomotorius, causing mydriasis ; on the heart mus- 
carine producing the same effect as stimulation of the vagus, while 
atropine prevents the action of the vagus and thus enables the influence 
of the sympathetic accelerator fibres to gain the upper hand, mus- 
carine causing contraction and atropine relaxation of bronchial 
muscles. Further, muscarine and pilocarpine cause violent contraction 
of the gastric and intestinal muscles and of the smooth muscles of 
other organs, while atropine in certain dosage abolishes the tone of 
these muscles. Muscarine and pilocarpine cause secretion in all true 
glands ; atropine inhibits it. As these drugs also act in a similar 
fashion on the glands of the skin, — although, as far as is at present 
known, they are innervated only by sympathetic and not by autonomic 
nerves, — we have here an apparent exception to the general law of 
their behavior. However, one can almost believe that this exception is 
actually only an apparent one, and that it will be explained when more 
has been learned of the innervation of these glands. 

The points at which these different drugs act are not completely 
known in all their details. This much, however, is certain, — viz., that 
they all act on the terminal nervous organs of the autonomic nerves, 
and that this common pharmacological behavior indicates that the 
different nerve-endings of this system belong together. 

Similar pharmacological — which is the same as to say similar chemical — 
reactions of organs indicate a homologous chemical structure, and consequently 
such may be assumed for all the sympathetic terminal nervous organs, and 
also for all autonomic ones. Moreover, the nerves of these two systems appear 
to differ also in respect to their points of origin in the central nervous system, 
these centres being also characterized by certain chemical or pharmacological 
reactions which are characteristic of them. Picrotoxin, obtained from Indian 
berries (Anamirta paniculata), in addition to producing other effects, stimu- 
lates all the cranial and sacral autonomic nerves, — the oculomotorius, the chorda 
tympani, the vagus, and the pelvicus, — this action being not peripheral but cen- 



VEGETATIVE NERVOUS SYSTEM 143 

tral (Griinwald). It thus appears that the autonomic centres all exhibit the 
same chemical reaction. This may -not be said of the sympathetic central organs 
with the same general application, for up to the present there are only a few- 
facts known which indicate that this is probably the case [Jonescu). 

From the above it may be seen that nicotine acts on all the ganglia 
of the entire vegetative nervous system, while epinephrin exerts its 
action only on the sympathetic nerve-endings. Besides the above- 
mentioned drugs many other substances act on the separate portions 
of the vegetative system. As, in all doubly innervated organs, the 
stimulation of one system and the depression of the other must pro- 
duce similar effects, it is evident that the same alterations of the func- 
tions of these organs may result from pharmacological actions exerted 
on different points. Thus, for example, dilatation of the pupil may be 
produced either by stimulation of the sympathetic nerve-endings in 
the iris by epinephrin, or by paralysis of the oculomotorius nerve- 
endings by atropine, or the action of the heart may be accelerated as 
a result of stimulation of the accelerator nerve-endings by large doses 
of caffeine, or by paralysis of the vagus nerve-endings by atropine. 
It is thus evident that unusually numerous and complicated pharmaco- 
logical actions on the vegetative nervous system are possible. 

BIBLIOGRAPHY 

Dale: Journ. of Physiol., 1900, vol. 34, p. 103. 
Elliott: Journ. of Physiol., 1905, vol. 32. 
Griinwald: Arch. f. exp. Path. u. Pharm., 1909, vol. 60. 
Jonescu: Arch. f. exp. Path. u. Pharm., 1909, vol. 60. 
Langley: Journal of Physiology, 1898, vol. 23, p. 240. 



CHAPTER V 

PHARMACOLOGY OF THE EYE 
PHARMACOLOGICAL REACTIONS OF THE RETINA 

The light-sensitive layers of the retina — i.e., the visual cells with 
their rods and cones — transmit their impulses to the layer of the retinal 
ganglion-cells through the bipolar cells, which may be looked upon as 
corresponding to the spinal ganglion-cells, while the retinal ganglionic 
layer may be considered as a portion of the gray matter of the central 
nervous system which has been pushed out into the periphery and from 
which impulses pass via the optic nerve into the brain, just as im- 
pulses pass from spinal ganglia through the conducting paths up into 
the higher portions of the central nervous system. 

This preliminary statement appears necessary in order that we may 
understand why, in the first place, many toxic substances which act on 
the retinal ganglia also produce changes in the optic nerve which 
arises from them,* in apparent contradiction to the behavior of the 
centripetal nerves whose sensory terminal organs in the periphery may 
be damaged without its being necessary that the nerve itself be in- 
jured, and why, in the second place, the retinal elements themselves 
are acted upon by pharmacological agents whose preponderating 
actions are ordinarily exerted only on the central nervous system. 

Drugs Relieving Retinal Hyperan^esthesia. — This is of signifi- 
cance for those cases in which the susceptibility of the retina is abnor- 
mally augmented or diminished by photophobia or by retinal ambly- 
opia. Drugs which are certainly able to moderate hyperesthesia of 
the retina in photophobia accompanied by severe pain are apparently 
not known. According to Simpson, if the eye be held immediately 
above chloroform its vapors relieve photophobia, and the same is stated 
to be true of carbonic acid gas (Binger-Thamhayn) . 

The symptoms of photophobia are due to stimuli which reach the centres 
through the trigeminus. They may occur even after previous section of the optic 
nerve and in the totally blind, and are, therefore, to be considered as due to a 
reflex occurring within the retina, which here behaves, as it were, as a segment 
of the spinal cord. They appear to be analogous to the algesias and hyperalgesias 
of particular regions of the skin which have been described by Head as occurring 
in diseases of the viscera whose innervation is connected with the same segment 
of the spinal cord as is that of the painful cutaneous area. However, this pain 
resulting from bright light is often due only to a spasmodic reflex contraction 
of the sphincter of the iris, and in such cases it disappears when atropine or 
homatropine is instilled. 

* In this connection, among others, may be mentioned the amblyopias due 
to toxic action of methyl alcohol, quinine, felix mas, pelletierine, and probably 
also in part those due to tobacco, ethyl alcohol, and carbon disulphide (Uhthoff). 
144 



RETINA AND IRIS 145 

Drugs Augmenting Retinal Excitability. — On the other hand, 
the excitability of the retinal elements may be certainly augmented 
by strychnine, which, as we know, possesses the power of increasing 
reflex excitability in general. Sharpness of vision of both the normal 
eye and of one impaired as a result of amblyopia may be temporarily 
increased by this drug. This action takes place chiefly in the periphery 
but also to a certain extent in the centres, and results in an improve- 
ment in the power of differentiating colors (Dreser) . This effect may 
he produced on one side only if strychnine oe injected into the temple 
or instilled into the eye {Filehne). It is just as difficult to determine 
whether such a temporary augmentation of the excitability of the 
retinal ganglionic organs can be of value in diseases of the eye as it 
is to judge of the value of the analogous employment of strychnine 
in motor pareses. 

Saxtonine. — A peculiar alteration of the perceptive retinal elements of 
caused by the anthelmintic santonin. About one-half hour after taking this drug, 
brightly illuminated objects appear violet, and a little later yellow. This is 
due to a primary stimulation followed by depression of the retinal cells which are 
susceptible to the violet rays of the spectrum. The central color sense (com- 
plementary perception of violet) remains (Knies) . 

BIBLIOGRAPHY 

Dreser: Arch. f. exp. Path. u. Pharm., 1894, vol. 33. 

Ellaby, Miss: Arch. d'Ophthalm., 1882, vol. 2, p. 532. 

Filehne: Pfluger's Arch., 1901, vol. 83. 

Grafe-Samisch : Handb., 1901, Literature. 

Knies: Arch. f. Augenheilk., 1898, vol. 37. 

Simpson, cited from Ringer-Tliamhayn : Handbuch, 1877. 

Uhthoff : Ueber die Augenstorungen bei Vergiftungen, Leipzig, 1901. 

PHARMACOLOGICAL ACTIONS ON THE IRIS AND THE 
CILIARY MUSCLE 

We possess a much more exact knowledge of the action of drugs 
on the motor organs of the internal eye, — i.e., on the muscles of the 
iris and on the ciliary muscle. 

The iris is made up of two sets of muscles, one set being arranged in the 
form of a ring while the other is composed of radiating muscle-fibres. The circu- 
lar muscle, the sphincter of the iris, is innervated by the autonomic post- 
ganglionic fibres coming from the oculomotorius, which send pre-ganglionic fibres 
1o the ciliary ganglion. The antagonistic radial muscle, the dilator of the iris, 
i.-, innervated by the sympathetic nerve coming from the superior cervical gan- 
glion, from which the post-ganglionic fibres pass to these muscles alongside the 
ciliary ganglion and via the carotid plexus. 

The contraction of the. ciliary muscles narrows the ring in which the lens 
is suspended so that owing to its own tension it can become more convex. The 
ciliary muscle receives tin; impulses which produce this effect through the cranial 
autonomic fibres of the oculomotorius, just as docs the sphincter of the iris. 

It is claimed by Morat and Doyon, and denied by Meeae and others, that 

nervous impulses arc received by the ciliary muscle through the sympathetic 

which produce the antagonistic effect of widening this ring and rendering the 

lens less convex. The negative results of the last-named authors cannot, however, 

10 



146 



PHARMACOLOGY OF THE EYE 



be considered as definitely decisive, because the range of accommodation of the 
animals used in their experiments is too slight (Hecse, Hess u. Heine). 

Certain drugs produce in both of these muscles stimulation or paralysis as 
should be expected from their different nerve supply. 

The centres of the autonomic oculomotorius which lie in the 
cerebrum may be affected by pharmacological agents so as to produce 
changes in the pupil, asphyxia for example causing a paralysis of these 
centres. Consequently, a sudden maximal dilatation of the pupil 
serves as one of the latest warnings of danger of asphyxia in the course 
of anaesthesia. 

Such dilatation of the pupil of central causation, due to inhibition 
of the oculomotorius, may result from psychic excitement, such as a sudden 
fright, or from direct electric stimulation of the cerebral cortex in the region 




-Red, sympathetic nerves; blue, autonomic or parasympathetic fibres 
from the oculomotorius. , 



of the gyrus sigmoideus or of the basal ganglia, and this may occur when either 
the trigeminal nerve, which contains the vasomotor nerves of the iris, or the 
superior cervical sympathetic ganglia or the cervical cord itself has been severed. 
This reflex dilatation of the pupil can, consequently, be explained only as due 
to a weakening of the tone of the oculomotorius centre, — i.e., as due to the 
stimulation of a central inhibitory mechanism (Braunstein) . If this inhibitory 
mechanism, which is ordinarily kept active by all sorts of sensory stimuli, 
becomes inactive as the result of cutting off all sensory stimuli, — as, for example, 
in natural sleep or that caused by chloral, — the tone of the oculomotorius centre 
is augmented and the pupil contracts. 



CENTRAL MIOTICS AND MYDRIATICS 147 

In all probability this central autonomic inhibitory mechanism is electively 
paralyzed by morphine, even in moderate doses which produce hardly any anal- 
getic effects. Consequently a more or less pronounced miosis is a constant symp- 
tom of the action of morphine. Atropine overcomes this morphine miosis 
promptly, but cocaine, whose action is only that of rendering the sympathetic 
nerve-endings more excitable, hardly alters it (personal communication of 
E. Fuchs ) . Both of these facts indicate the correctness of the explanation of the 
morphine miosis given here. It would appear that the autonomic centre of the 
cardiac vagus is affected in an analogous fashion, and this is probably, therefore, 
an explanation of the slowing of the heart caused by morphine (Danilewski u. 
Lawrinoioitsch) . This hypothetical inhibitory centre may be looked upon as being 
a controlling mechanism for the sympathetic nerves, which acts in opposition 
to and is opposed by corresponding centres of the cranial autonomic nerves so 
that they maintain a combined control or balance, just as is the case with the 
motor centres controlling the agonistic and antagonistic voluntary muscles. (See 
p. 16 and Fig. 3, p. 17.) 

In all probability, therefore, the miosis of sleep and of morphine 
poisoning is due to a markedly augmented — i.e., uninhibited — tone of 
the oculomotorius centre which normally, in the waking state, is under 
the influence of strong inhibitory impulses from the cerebral cortex, 
the corpora quadrigemina, and the corpora striata (Braunstein) . 

Miosis due to excitation of this autonomic oculomotorius centre is one of 
the symptoms produced by the action of certain central convulsants, particularly 
picrotoxin ( Griinicald) . This is of some interest, inasmuch as this drug elec- 
tively excites not only the centres of the autonomic oculomotorius but also all 
other centres of the autonomic nerves known to us, those of the chorda, vagus, 
pelvicus, etc., from which the conclusion may be drawn that, like their terminal 
organs, the motor centres controlling the agonistic and antagonistic voluntary 
muscles have a common chemical structure. 

Mydriasis due to paralysis of the oculomotorius centre occurs as 
a pathognomonic symptom in certain poisonings, — for example, those 
caused by meat, fish, mussels, cheese, and particularly by that caused 
by sausage, the so-called botulismus. Here, however, not only the 
autonomically innervated internal muscles of the eye, the iris and the 
ciliary muscle, but almost always the external muscles, as well as the 
levator palpebral, are affected so that ptosis and usually double vision 
result. This is a readily recognized difference between the effects of 
such poisonings and of all other poisonings which cause a mydriasis 
induced peripherally (TJhthoff). 

BIBLIOGRAPHY 

Braunstein: Zur Lehre d. Innervation d. Pupillenbewegung, Wiesbaden, 1894. 

Danilewski U. Lawrinowitsch: loc. cit. 

Grtinwald: Arch. f. exp. Path. u. Pharm., 1900, vol. 60. 

Heese: PiliiL"T'> Arch.. 1892, vol. 52, 

Bese u. Urine: Criife's Arch., 1898. vol. 46. 

I'litliulT: Ueber die Augenstorungni 1 -<•[ Venriftungen, Leipzig, 1901. 

MIOTICS ACTING IN THE PERIPHERY 

The autonomic nerve-endincrs in the sphincter of the pupil and 
in the ciliary muscle are stimulated by the drugs of the physostigmine 
group, of which physostigmine itself is the most important. 



148 PHARMACOLOGY OF THE EYE 

PHYSOSTIGMINE OR ESERINE 

Physostigmine, or eserine, is an alkaloid occurring in the calabar bean, the 
fruit of Physostigma venenosum. With sulphuric and salicylic acid it forms 
readily crystallizable, colorless, hygroscopic salts, whose aqueous solutions after 
a time acquire a red to dark cherry-red color, as the result of the formation of 
an inactive oxidation product, rubreserine. The calabar bean contains another 
alkaloid, eseridine, with similar action, and still another, calabarine, which 
possesses a convulsant action. 

Miotic Action. — If a few drops of a 1 per cent, solution of eserine 
be instilled into an eye, after about 20 minutes the pupil becomes 
narrow and the ciliary muscle begins to contract. The near point and 
far point of vision approach each other, and after half an hour the 
far point approximates the normal near point. After about two hours 
the spasm of accommodation passes off, but the pupil remains narrow 
for a considerable time longer. At this time, however, the accommo- 
dation is still more excitable than normally and the slightest voluntary 
effect produces a most extreme degree of accommodation (Earner). 

Apparently the action of eserine on the pupil could be explained 
just as well by a paralysis of the dilator as by a spasm of the con- 
strictor mechanism of the iris, or it might be attributed to both of these 
effects occurring at the same time. However, it may be experimentally 
shown that the dilator of the iris retains its excitability, for, if the 
cervical sympathetic be stimulated in an animal whose pupils are 
maximally contracted by eserine, they dilate in normal fashion. This, 
however, does not prove that the tone of the sympathetic nerve-endings 
in the iris has not perhaps been weakened by eserine. This is, in fact, 
probable, inasmuch as apparently every stimulation of the sphincters 
is necessarily accompanied by a relaxation of the dilators, and vice 
versa (Way month Reid). 

The point at which eserine acts is thus seen to he in the sphincter 
of the iris and in all probability in the terminal organs of the auto- 
nomic oculomotorius, for under certain conditions it can produce con- 
traction of the pupil even after section of the short ciliary nerves or 
after removal of the ciliary ganglion, but it no longer produces this 
effect if sufficient time has elapsed since their section to permit the 
nerve-endings to degenerate. Denned more exactly, its action does not 
\consist in a direct excitation of these elements, but in the production 
of a very marked augmentation of their excitability. This appears to 
be indicated by the observations, described below, on the lowering of 
the threshold value for stimuli which is caused by eserine. It is also 
in agreement with the fact that after previous section of the oculo- 
motorius, — i.e., after abolition of stimuli from this centre, — eserine 
produces no apparent effects, — i.e., does not overcome the existent 
sympathetic tone. Only after section of the sympathetic is it effective 
and able to narrow the pupil, for then the chemical stimuli furnished 
by the blood are sufficient to stimulate the terminal organs of the 



MIOTICS ACTING IN PERIPHERY 



149 



oculomotorius if they have been rendered over-excitable by eserine. 
It is important to emphasize this fact, because of the action of eserine 
in similarly increasing the excitability of the other autonomic (para- 
sympathetic) terminal organs (see below). 

Action on Accommodation. — This action of eserine, that of ren- 
dering the oculomotorius nerve-endings in the ciliary muscle more 
excitable, is responsible for the facilitation of accommodation or the 
spasm of accommodation which may result from its employment. As 
a result, in addition to rendering it difficult or impossible to see clearly 
any objects lying beyond the near point, eserine causes one to over- 




Fig. 9. — Monkey's eye after atropir 



Iris thickened and retracted 
(Heine). 



estimate their size (macropsia), because, on account of the slighter 
effort at accommodation they are held to be more distant and, as the 
angle of vision remains the same, they are held to be larger. 

Effect on Intra-ocular Tension. — Another result of the action 
of physostigmine in the eye is much more important; this is the 
diminution of the intra-ocular pressure (Laqucur). This is chiefly 
the result of the widening of Fontana's spaces which results from the 
concentric movement inward of the ciliary body, as a consequence 
of which the outward passage of vitreous fluid is markedly facilitated. 
Figs, f) and 10, representing preparations of monkey's eyes fixed, one 
with the ciliary muscle relaxed and the other will) this muscle con- 
tracted, illustrate this action. This effect, is aided by the contraction 



150 



PHARMACOLOGY OF THE EYE 



of the internal blood-vessels of the eve caused by eserine, which thus 
lessens the secretion of the vitreous humor (Laqueur) . 

According to Gronholm, in rabbits this action on the vessels is the only 
cause of the diminution of pressure. Knape, on the other hand, found that 
eserine, like atropine, always caused an active hyperemia of the rabbit's iris and 
no alterations in the blood-vessels of the fundus. Moreover, in his experiments on 
the normal eye, which were carried on with the observation of every precaution 
against error, he never, with the exception of very temporary variations at first, 
was able to observe any alteration of the intra-ocular tension, neither diminution 
in eserine miosis nor an increase in atropine mydriasis, observations which are 
explained by the assumption that the regulatory mechanism of the normally 
functioning eye prevents such effects. When this is disturbed, however, contrac- 
tion or relaxation of the iris produces changes in the intra-ocular tension. 

In the treatment of glaucoma, eserine may consequently serve to 
render iridectomy possible, not only by spreading out the iris but 
also by directly diminishing the pathologically increased tension. 




expanded 



Iris pulled forward and flattened 
Fig. 10. — Monkey's eye after eserine (Heine). 

In connection with the instillation of y 2 -l per cent, solutions of 
physostigmine in the eye, it should be noted that the greater portion 
of the instilled fluid reaches the nose and mouth through the lachrymal 
canals, and that it thus may cause a systemic poisoning. This may be 
prevented by closure of these canals for a time by pressing on them 
with the finger, a procedure which may be adopted when any medicinal 
solutions are applied to the eye. 

Other Actions of Physostigmine on the Autonomic Nerve-endings. — 



MIOTICS ACTING IN PERIPHERY 151 

The same augmentation of excitability already described as produced 
by eserine in the oculomotorius mechanism- is produced by it in all 
other autonomic (parasympathetic) nerve-endings, causing augmen- 
tation of the excitability of the cardiac vagus (Winterberg) , of the 
intestinal vagus, chorda tympani, and N. pelvicus (Loeivi u. Mansfeld) , 
and also of the nerve-endings in the sweat-glands. 

Consequently, with the systemic action of physostigmine there is 
increased flow of the tears and saliva, increased secretion of the mucous 
and bronchial glands, profuse sweating, increased contraction of the 
muscles of the bronchi, stomach, and intestines, vomiting and violent 
purging, as also spasmodic contractions of the bladder and at times of 
the uterus, and finally a slowing of the action of the heart. All these 
effects may be overcome by sufficiently large doses of atropine. Thera- 
peutically we make use only of its actions on the intestine in conditions 
of atony, tympanites, etc. 

Action on Motor Nerves of Striped Muscles. — Further, physostig- 
mine increases the excitability not only of the above-mentioned auto- 
nomic nerve-endings but also that of the nerve-endings supplying volun- 
tary muscles. The excitability of these peripheral terminal organs 
is so increased that previously subliminal stimuli become effective. If 
the motor nerve-endings have been paralyzed by curare to such a 
degree that even the very strongest faradic stimulation of the nerve 
produces no effect, the excitability may be again restored by eserine 
and then again completely paralyzed by large doses of curare. This 
explains why curarized animals which are already suffering from 
asphyxia begin to breathe again after the injection of eserine and are 
again able to move (see curare, p. 11). 

Harnack and Witkowski, by investigating the strength of the directly applied 
induction current necessary to produce contractions of the muscles, have been 
able to show that the excitability of curarized frog muscles is increased by eserine, 
and attribute this result to an action on the contractile substances of the muscles. 
It is possible, however, that this effect may be due to an action on nervous ele- 
ments lying peripherally to the point at which curare acts, for the direct faradic 
stimulation of curarized animals probably does not act directly on the muscle-cells 
themselves or upon these alone, but also on the terminal nervous organs which lie 
beyond that part of the nerve which is paralyzed by curare [Eerzen, Julvyko), 

Moreover, the physostigmine produces another very striking and 
theoretically important effect in the striped muscles, — namely, fibril- 
lary or, more correctly, fascicular twitchings which extend over the 
whole body and resemble violent shivering from cold. This effect 
iimisI be due to an action on the nervous terminal organs, for, after 
section of the nerves, these twitchings continue although with dimin- 
ished intensity, but may no longer be induced in the muscles whose 
nerves have been divided and have degenerated (Magnus). They are 
not inhibited by curare, but are readily stopped by small doses of 
atropine (RotKberger) and by lime suits (Loewi). 

These phenomena suggest thai autonomic nerve-endings play a role 



152 PHARMACOLOGY OF THE EYE 

in producing this twitching: of the muscles, and that, therefore, besides 
spinal motor nerves, not only sympathetic vasomotor nerves but also 
motor autonomic (parasympathetic) fibres supply the voluntary mus- 
cles, which last-mentioned nerves play a role in the regulation of heat. 

It also appears that in these two systems, the autonomic or parasympathetic 
and the spinal, we are dealing with a reciprocal antagonism between eserine and 
atropine in one system and eserine and curare in the other, in both of which cases 
physostigmine is the weaker antagonist. We may understand this by conceiving 
that eserine and atropine exhibit a tendency to enter into a reversible chemical 
combination with the same substances in the nerve-endings, these different 
drugs causing opposite effects on the functions and possessing a chemical affinity 
for these substances of very different intensity, so that physostigmine, with less 
affinity for these substances, may be forced out from these combinations by very 
small quantities of atropine or curare, both of which possess much stronger 
affinities to it, in a fashion similar to that in which oxygen is forced by carbon 
monoxide out of its combination with haemoglobin. It is, however, possible, and 
in fact more probable, that, at any rate for physostigmine and atropine, in the 
iris the points at Avhich the action is produced are not the same. 

The elements in the iris which are acted upon by eserine disappear with the 
degeneration of the nerves, which follows destruction of the short ciliary nerves 
or the ciliary ganglion, but there still remain in the iris certain excitable elements 
which are not purely muscular in their nature but which seem to consist of a 
myoneural intermediary substance. This intermediary substance is not suscep- 
tible to the action of eserine, but is excited by pilocarpine (see p. 153) so that 
miosis is induced. Atropine overcomes this action of pilocarpine, and conse- 
quently in all probability produces its effects by acting on this intermediary 
substance (Anderson ) . With moderate atropinization, therefore, a block is 
formed through which the normal stimulating impulses of the oculomotorius 
cannot pass, but which is passed by these stimuli when they are increased by 
the action of eserine. Complete atropinization, however, can prevent this passage 
of such stimuli to the contractile substance, and it is thus evident that the 
antagonism between atropine and eserine is not reciprocal in the strict sense. 

Actions on Heart and Central Nervous System. — In conclusion it 
should be mentioned that eserine also produces certain stimulating 
effects in the cardiac muscle (Winterberg) , and that the augmentation 
of the nervous excitability produced by eserine is not limited to the 
peripheral organs but manifests itself also in certain portions of the 
brain and cord. The respiration is strengthened and deepened, as a 
result of an action on the peripheral vagus endings in the lungs (Bezolcl 
and Goetz) and also of a direct stimulation of the medullary respira- 
tory centre (Rothberger) . The motor cortical centres are also ren- 
dered more excitable, an effect which is especially marked in the 
presence of a tendency to epileptic convulsions (Harnack u. 
Witkoivski). 

[The fairly wide-spread use of physostigmine in the treatment 
of tetanus is not justified by our knowledge of its pharmacological 
actions. On the contrary, all that we know of it forbids its employ- 
ment in such conditions. — Tr.] 

BIBLIOGRAPHY 

Anderson: Journ. of Phys., 1905, vol. 32, 190G, vol. 33. 

Gronholm: Grafe's Arch., 1900, vol. 49, p. 620. 

Hamer, 18G3: cited bv Snellen in Griife-Samiseh's Handbuch, 1905. 



MIOTICS ACTING IN PERIPHERY 153 

Harnack u. Witkowski: Arch. f. exp. Path. u. Pharm., 1876, vol. 5. 

Heine: Grafe's Arch. f. Ophthal., 1S99, vol. 49, No. 1. 

Herzen: Intermed. des Biolog., 1898, vol. 15. 

Joteyko: Inst. Solvay, Trav. 4, 1901. 

Knape: Arb. Physiol. Inst. Helsingfors. Festschr., 1910, p. 215. 

Laqueur: Arch. f. Ophth., 1877, vol. 23, p. 149. 

Loewi u. Mansfeld: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 180. 

Magnus: Pfliiger's Arch., 1908, vol. 123. 

Rothberger : Pfliiger's Arch., 1901, vol. 87. 

Wavmouth Reid: Journal of Phys., 1895, vol. 17. 

Winterberg: Ztschr. f. exp. Path. u. Ther., 1907, vol. 4, here lit. 

PILOCARPINE 

Pilocarpine acts on the iris and ciliary muscle similarly to physo- 
stigmine, causing miosis, spasm of accommodation, and diminution of 
intra-ocular tension; but all these actions are weaker and less per- 
sistent and are produced only by much stronger solutions (4 per cent.) 
(Jaarsma) . A difference in their actions which, while not particularly 
important, is theoretically a fundamental one, is that pilocarpine does 
not, like eserine, increase the excitability of the nerve-endings, but 
actually directly stimulates them. The miosis produced by it occurs 
even after abolition of the central innervation by post-ganglionic sec- 
tion of the oculomotorius and in spite of a persisting antagonistic 
action of the sympathetic. With the passing off of its visible effects, 
the latent increased excitability does not remain, as is the case with 
physostigmine, but in place of it there is a paresis of the oculomotorius 
nerve-endings, the pupils becoming wide or normal (Harnack u. 
Meyer), the accommodation remaining impaired, and the near point 
being rendered more distant (Falchi). The other actions of pilo- 
carpine on the autonomic terminal nervous organs are also to be 
considered as due to a direct excitation. 

In respect to their actions on the eye and on most of the other autonomic 
cally innervated organs, nicotine, muscarine (Schultz), and choline (F. Midler) 
resemble pilocarpine, as does arecoline, a base obtained from the betel-nut. The 
hydrobromate of this base, when instilled into the eye in 1 per cent, solution, 
produces miosis and a passing spasm of the accommodation, which is followed 
by slight mydriasis {Marine, Lavagna, Frohner). 

BIBLIOGRAPHY 

Falchi: Giorn. della R. ace. di med. di Torino, 1885. 

I'.r.liner: Monatsh. f. prakt. Tierheilkundc, 1894. 

Harnack u. Meyer: Arch. f. exp. Path. u. Pharm., 1880, vol. 12. 

• biarsma: Diss. Leiden., 1880. 

Lavagna: Therap. Afonatsh., 1895, i>. :!<;.">. 

Mamie: GSttinger Nachrichten, 1889. 

Mflller, P.: PflUger'fl Arch., 1910, vol. 134, p. 289. 

Schultz: Arch. f. Physiol., 1898. 

ATROPINE 
Atropine and its congeners produce the opposite — i.e., a paralytic — 
effect on the autonomically innervated organs. This alkaloid, with 
the empiric formula C 17 H 28 N0 8 , occurs in all the solanacea?. 



154 PHARMACOLOGY OF THE EYE 

In its constitution it is a basic ester, which may be decomposed by alkalies 
or acids into a basic alcohol, tropine, and an aromatic acid, tropaic acid. 

CwH^NOs + H 2 = CgH ie NO + COOH.C 8 H 8 OH. 

Atropine. Tropine. Tropaic acid. 

According to Willstatter, its constitution may be represented as follows: 



H H 2 

H 2 C C C 



CH 2 OH 
>NCH 3 ;CHO-CO-C-H 



-C- 



C 6 H 5 



H 2 C H H 2 

Tropine. Tropaic acid. 

For two reasons this formula possesses for us considerable interest. The 
basic portion, tropine, is closely related to ecgonine (see p. 121) : the basic portion 
of cocaine, which is also an ester and which in many particulars exerts actions 
similar to those of atropine. As the formula shows, tropaic acid contains 
an asymmetrical carbon atom, and occurs in three modifications, a laevorotatory, 
a dextrorotatory, and a racemic inactive one, and forms correspondingly different 
tropeins. Ordinary atropine is optically inactive, being formed of a mixture 
of lsBVorotatory and dextrorotatory bases, of which the former is identical with 
the natural 1-hyoscyamine. This 1-hyoscyamine has twice as strong an action 
on the autonomic nerve-endings as has atropine, a fact which is accounted for 
by the further fact that r-hyoscyamine is almost without action on these organs 
{Cushny). The closely related alkaloids 1- and r-scopolamine exhibit the same 
remarkable difference in their physiological actions (Cushny), and similar 
differences are noted in connection with other drugs, as, for example, in 1- and 
r-epinephrin. The reason of this different physiological behavior of optical 
isomeres is unknown. 

Mydriatic Action. — If a drop of a 1 per cent, solution of atropine 
be instilled into the conjunctival sac, after about 15 minutes the pupils 
commence to dilate, and about the same time the near point moves out, 
which action continues until the accommodation is completely 
paralyzed. Both of these actions are due to paralysis of the autonomic 
oculomotorius nerve-endings in the sphincter of the iris and in the 
ciliary muscle, for, when the oculomotorius is stimulated inside the 
skull or the short ciliary nerves are stimulated in the orbit, no effect 
is produced on the iris of an atropinized eye although the sphincter 
muscle still reacts well to stimulation (Schultz). 

In so far as paralysis of the sphincter in all probability increases 
the tone of the antagonistic dilator, atropine also causes an increase 
of the tone or of the excitability of the sympathetically innervated 
dilator. However, this action is neither very apparent nor important, 
for after even the strongest atropinization it is always possible to dilate 
the widened pupil still farther by central electrical or peripheral 
pharmacological stimulation of the sympathetic nerves. When the 
normal central inhibition of the oculomotorius is abolished, as is the 
case in sleep (Rudolph) or in chloral narcosis (Levinstein, TJlrich), 



ATROPINE 155 

the pupil already dilated by atropine dilates still further. Even this, 
however, does not indicate that atropine directly stimulates the sympa- 
thetic nerve-endings, but only that it depresses the cranial autonomic 
(parasympathetic) oculomotorius endings. 

Duration of the Action. — The effect of atropine in the eye persists 
for a number of days, the paralysis of accommodation disappearing 
completely only at the end of 2-3 days, and the mydriasis only after 
8-10 days. In old people the effect on the iris is slight, while in 
presbyopia it is almost nil. 

Other Actions in the Eye. — The deceptive micropsia produced 
hy atropine is explained in an analogous fashion to the macropsia pro- 
duced by eserine. As the wide non-reacting pupil permits the unhin- 
dered entrance of bright light, dazzling and photophobia result. 
Through the retraction of the iris the spaces of Pontana are so distorted 
that the exit of fluid from the chamber of the eye is hindered, and 
consequently the intra-ocular tension is increased, so that in patients 
with a disposition to glaucoma an acute attack may be precipitated 
(see p. 150). 

Atropine exerts no action upon the oculomotorius nerve-endings in the 
iris of birds and reptiles in which the iris is composed of striped muscle-fibres. 
These nerve-endings, however, are paralyzed by curare, but not by numerous 
cmaternary ammonium bases which in other particulars act like curare, but 
on the contrary they are strongly stimulated by them. There is, therefore, no 
essential similarity in the behavior of the striped muscle of the bird's iris and 
that of the other striped muscles (H. Meyer). 

Uses in Ophthalmology. — Atropinization of the eye by abolishing 
the accommodation renders possible the exact determination of the 
refraction, and, by widening the pupils, facilitates ophthalmoscopic 
examination of the lens and of the fundus and the performance of 
operations on the lens, etc. Moreover, the complete quieting of the 
internal muscles of the eye produces most favorable effects in painful 
spasm of the accommodation and in all inflammatory conditions such 
as iritis, etc. This latter action is augmented by a slight anesthetic 
action on the sensory nerve-endings of the cornea and iris. For these 
various reasons, atropine has become one of the drugs most frequently 
used in ophthalmology. It should, however, be noted that the repeated 
instillation of atropine into the eye is followed at times by a conjuncti- 
vitis ;in(| more rarely by oedema of the lids (Uhihoff). The cause of 
this harmful action is not known. 

Systemic Actions. — The peripheral action of atropine is exerted 
on all parasympathetic terminal nervous organs, and consequently, 
generally speaking, it depresses the motor activity and the tone of 
smooth muscles as well as the secretory activity of glands. Not only do 
the mouth and skin become dry as a result of the diminution of the 
secretions, but the secretion of the gastric and intestinal glands also 
is diminished. In the heart the inhibitory vagal nerve-endings are 
paralyzed, so thai the hear! heats very rapidly and the blood-pressure 



156 PHARMACOLOGY OF THE EYE 

rises, while the skin becomes red as a result of the marked dilatation. 
of the small cutaneous vessels and the body temperature rises {Moral 
et Doyon). 

Acute Poisoning. — From these various actions arise the character- 
istic symptoms of acute atropine poisoning, such as is not infrequently 
observed particularly in children who have eaten belladonna berries. 
These symptoms are a scarlet-red, dry, hot skin, very rapid breathing' 
and pulse, and dilated pupils, with which are associated active excite- 
ment, with delirium, laughing or crying, marked motor activity or even 
convulsions. As a result of the paralysis of part of the swallowing 
muscles, there is an inability to swallow. Finally central paralysis 
develops, causing stupor, an irresistible tendency to sleep, and pro- 
found coma that may pass over into death. 

Even a few milligrammes of atropine cause in man very pro- 
nounced and often violent symptoms of poisoning, but without danger- 
ous results, which latter occur only after decidedly larger doses. The 
lethal dose for adults is stated to be 0.1 gm., and this is probably 
too small, but in children 0.01 gm. may cause death. 

In addition to the chemical and particularly the pharmacological reactions 
of atropine, the blue fluorescence of the urine caused by the glucoside scopoletin, 
which is present in belladonna, as well as in the Scopola japonica, may be of 
assistance in recognizing and proving poisoning produced by these plants 
(A. Paltauf). 

Treatment. — The most essential point in the treatment of atropine 
poisoning is the thorough washing out of the stomach. If a condition 
of marked excitement be present, morphine should be administered. In 
the dangerous comatose stage the various cerebral stimulants, caffeine, 
strychnine, and camphor, may be administered, and it is probable that 
free infusion of warm Ringer's solution or of normal saline solution 
may be of value by helping to dilute and to eliminate the poison. As 
the bladder is usually paralyzed, it must be emptied by catheter. 

Chronic poisoning may result from the long-continued medicinal use of 
atropine or the related alkaloids, and is characterized by. loss of appetite and 
emaciation (v.'Anrep, Marandon de Montyel). It is possible that such poison- 
ing is chiefly due to a persistent or at least frequently repeated paralysis of the 
glandular secretions. 

Certain herbivorous animals, particularly goats, sheep, and rabbits, show 
a very remarkable resistance to atropine. With rabbits this is due to the fact 
that their blood detoxicates atropine (Fleischmann) , as does also the liver 
(Cloetta). Horses and cattle are much more susceptible, but dogs of medium 
size support doses of as much as 1.0 gm. or more, while cats die after receiving 
a few centigrammes. 

Therapeutic Uses. — In addition to its use in ophthalmology, 
atropine may be employed for its therapeutic effects in all those 
conditions in which its actions upon the terminal organs of the auto- 
nomic (parasympathetic) nervous system are indicated. For example, 
for the purpose of inhibiting the secretion of various glands, in pro- 
fuse sweating, salivation, or lachrymation, in spasmodic conditions of 



ATROPINE SUBSTITUTES 157 

the organs containing smooth muscles, such as the bronchi, stomach, 
intestines, gall-bladder, urinary bladder, uterus, etc., or in conditions 
in which there is an abnormal stimulation of the cardiac vagus. It may 
also be employed to stimulate the central nervous system, particularly 
the respiratory centre, as in morphine poisoning (E. Reichert). 

Preparations. — In addition to atropine sulpate (0.0005-0.001 gm. (!) per 
dose, 0.003 gm. ( ! ) per diem ) , various galenic preparations of belladonna, hyo- 
scyamus, etc., are used in medicine. The extracts contain 1-1% per cent, alka- 
loids, of which, however 1-hyoscyamine makes up the greater portion and 
atropine the lesser. In hyoscyamus, in addition to hyoscyamine there are small 
amounts of hyoscine or scopolamine, which accounts for its more pronounced 
sedative action. 

SUBSTITUTES FOR ATROPINE 

Homatropine, a synthetically prepared ester of tropine with man- 

delic acid, 

/OH 
C 6 H5CH< 

x COOH, 

has qualitatively the same pharmacological action as atropine but is 
much weaker. It is widely employed as a mydriatic, causing a more 
prompt but less lasting mydriasis than atropine. 

Scopolamine, or hyoscine, has also been used as a mydriatic in 
1 / 10 - 1 / 5 per- cent, solutions, but is more usually employed as a narcotic 
(see p. 27). It is atropaic acid ester of scopoline. 

Eumydrine. — By the addition of a methyl group the tertiary 
atropine may be transformed into the quaternary base, methyl atropi- 
num, the nitrate of which has been introduced as a mydriatic under 
the name eumydrine. In it the general actions on the central nervous 
system have been markedly weakened while the local effects in the eye 
are retained (Lindenmeyer) . 

Euphthalmine, C 17 H 2r N0 3 , the hydrochloride of the mandelic acid 
ester of methylvinyldiacetone-alkamine, is a synthetically prepared 
alkaloid, which, like atropine, paralyzes the oculomotorius endings, 
but only in much stronger solutions (5-10 per cent.) {Treutler). 

BIBLIOGRAPHY 

v. Anrep: Pfliiger's Arch., 1880, vol. 21. 

Cushny: Journ. of Pliys., 100:3, vol. 30; 1005, vol. 32. 

Gadamer: Arch. d. Pharm., 1901, vol. 239, p. 204. 

Levinstein: Berl. klin. W., 1870, No. 27. 

Lindenmeyer: Berl. klin. Woch.. 1903, No. 47. 

Marandon de*Montyel: Bull, de Ther., Feb. 25, 1804, vol. 126. 

Meyer, II.: Arch. f. exp. Path. u. Pharm., is 1 .):-,, vol. 32. 

Morat et Dovon: Compt. rend. d. 1. Soc. Biol., 1802. 

Paltiiuf, A.: Wien. klin. Woeh., 1888, No. 5. 

Reichert, E.: The Therap. Monthly, Philad., L901. 

Rudolph: Zentralbl. f. klin. Med., 1892, No. 40, p. 833. 

Bohultz: Engelmann's Arch., 1898, lit. here. 

Treutler: Klin. Mon. f. Augenheilk., 1897, p. 285. 

Uhthoff, Grafe-Samisch's Bandb., 1901, vol. 11. chap. 22, lit. here. 

Ulrich: Arch. f. Ophth., 1887. vol. 33, p. 2. 

Waymouth Reid: Journ. of Phys.. L895. vol. 17. 



158 PHARMACOLOGY OF THE EYE 

COCAINE 
The vasoconstrictors of the eye and the nerves supplying the 
radial muscles of the iris and the smooth muscles of the lids (Muller's 
muscle) are derived from the sympathetic system. Their nerve- 
endings are all stimulated if a solution of cocaine be instilled into the 
conjunctival sac, but, as cocaine, when thus applied, does not reach the 
retinal vessels, constriction has been observed only occasionally in cases 
of general poisoning by cocaine (Uhthoff). On the other hand, the 
vessels of the conjunctiva and the iris are strongly constricted and 
the pupils dilated while the palpebral opening is somewhat widened. 
The mydriasis is not maximal and the iris still reacts to light, although 
to a somewhat limited extent, indicating that the function of the 
oculomotorius nerve-endings has not been abolished. A further proof 
that this is so is furnished by the positive effect in the cocainized eye of 
stimulating this nerve intracranially. Accommodation also remains 
almost completely normal. Only after long-continued bathing of the 
eye with a strong (5 per cent.) solution of cocaine is the excitability 
of the oculomotorius nerve-endings abolished. 

If the sympathetic is divided peripherally to the superior cervical ganglion, 
for a time cocaine still dilates the contracted pupil, but if after a time degenera- 
tion of the sympathetic nerve-endings has occurred, cocaine no longer produces 
any noticeable effects; consequently, it may be concluded that its action is 
confined to the nervous element only (Schultz). 

As cocaine paralyzes the sensory trigeminal nerve-endings of the cornea 
and conjunctiva, it might be thought that the mydriasis produced by it is 
due to the abolition of sensory stimuli and to a failure of the reflex contractions 
of the iris dependent thereon. This explanation, however, is shown to be wrong 
by the fact that other local anaesthetics, such as holocaine, ^-eucaine, etc., do 
not cause any mydriasis. 

Effects on Intra-ocular Tension. — As a. rule, cocaine diminishes 
intra-ocular tension, probably on account of its power of constricting 
the vessels of the ciliary body of the iris, from which the fluid of 
the aqueous chamber is derived. However, the retraction of the iris by 
narrowing the canals of Schlemm tends to oppose this diminution of 
the intra-ocular tension and may, in fact, particularly in patients suf- 
fering from glaucoma, at times cause an acute attack of glaucoma 
(Uhthoff). 

Uses in the Eye. — Since its introduction by Roller, cocaine has 
come to be a drug which could hardly be spared in ophthalmology, 
for it very quickly produces a mydriasis lasting only for a few hours, 
anaesthesia of the cornea and conjunctiva, and anaemia of the ocular 
tissues. Its value here is somewhat lessened by its liability to damage 
the cornea, diffuse opacities of the cornea being quite readily caused 
and the healing of wounds of the cornea being retarded by it. 

That the abolition of the function of the sensory trigeminal nerve-endings 
may be a direct cause of trophic disturbances, if the blood-vessels of the eye be 
constricted, is demonstrated by the fact that a neuroparalytic keratitis may result 



EPINEPHRIN , 159 

from the simple removal of the Gasserian ganglion, including the vasodilator 
nerves of the anterior eye which run in the ramus ophthalmicus, but if at the 
same time the cervical sympathetic and, with it, tne vasoconstrictors of the eye 
are divided, no changes occur in the cornea (SpalUta). In man, however, because 
of the consensual closure of the lid, keratitis does not usually occur after one- 
sided extirpation of the Gasserian ganglion (Krause). 

Ephedrine and pseudo-ephedrine (Giinsbitrg), alkaloids prepared 
from Ephedra vulgaris and fi-tetrahydronaphthylamine (Stern), act 
on the dilators of the iris and on Muller 's muscle similarly to cocaine. 

BIBLIOGRAPHY 

Giinsburg: Virchow's Arch., 1891, vol. 124, p. 75. 
Koller: Wien. med. Woch., 1884, No. 43, 44. 
Krause: Miinchn. med. Woch., 1895. 
Schultz: Dubois' Arch. f. Physiol., 1898. 
Spallita: Arch, di Ottalm., vol. 2, No. 1, 1884. 
Stern: Virchow's Arch., 1889, vols. 115 and 117. 
Uhthoff: loc. cit. 

EPINEPHRIN 

Epinephrin and the related synthetic compounds (Loewi u. Meyer) 
act upon those elements of the eye which are innervated from the 
sympathetic system in the same fashion as does very strong stimulation 
of the sympathetic nerve (Wessely). Fractions of a milligramme 
injected intravenously cause a very pronounced mydriasis, which, 
however, lasts but a few seconds, and may even cause a momentary 
increase in the dilation of a pupil already maximally dilated by 
atropine (Leivandoivsky) . At the same time the eyeball is protruded 
and the vessels of the eye are constricted. "When instilled into the 
conjunctival sac in a strength of 1 : 1000 or even of 1 : 10,000, epi- 
nephrin powerfully constricts the conjunctival vessels, but, as a rule, 
in man causes no noticeable mydriasis, and also none in dogs and cats, 
but does so in rabbits and particularly in frogs (W. H. Schultz, 
Meltzer u. Aucr). If, however, the sympathetic nerve-endings of the 
iris are themselves abnormally excitable or are less inhibited by the 
antagonistic autonomic oculomotorius mechanism than normally, the 
instillation of epinephrin causes a distinct or pronounced mydriasis. 
This is the case in man in many cases of Basedow's disease, in which 
there is an increased excitability of the sympathetic innervation, and 
also in cases with insufficiency of the pancreas, such as severe diabetes 
in man, or in dogs and cats in which the pancreas has been extirpated. 
This pupillary reaction to epinephrin may consequently in certain 
cases have some diagnostic significance (Loewi). 

The terminal organs of the sympathetic nerve are also more excitable if 

they have been separated from their centre, the superior cervical ganglion, and 

consequently in such case the conjunctival instillation, which is ordinarily 

without ell'ect, or the subcutaneous injection of epinephrin may cause in rabbits 

a pronounced and rather lasting mydriasis i I/.7/:. ;■ and luer). 

The susceptibility of the entire sympathetic motor mechanism to epinephrin 
may be enormously increased by the administration of cocaine. Doses of cocaine. 



160 PHARMACOLOGY OF THE EYE 

which by themselves produce no marked influence on the iris of the cat or dog, 
60 alter the physiological condition of this organ that the instillation of 
epinephrin causes a pronounced mydriasis. This synergistic effect is still more 
clearly shown in connection with the action of these two drugs on the sympathetic 
innervation of the intestine and bladder and on the vasoconstrictors. It is conse- 
quently very probable that those actions of cocaine, which we call stimulation of 
the sympathetic nerve-endings, are essentially due to a specific sensitization of 
the motor sympathetic nerve-endings for the epinephrin, which is always present 
in the blood, although normally in subliminal amounts (Frohlich u. Loewi) . 

Its local vase-constricting action on the conjunctival vessels and 
also, when injected subconjunctivally, on the vessels of the iris and 
ciliary body is very useful in the practice of ophthalmology, particu- 
larly when it is used in combination with cocaine. 

BIBLIOGRAPHY 

Frohlich u. Loewi: Arch. f. Exp. Path. u. Pharm., 1910, vol. 62, p. 159. 

Lewandowsky: Zentralbl. f. Physiol., 1899, vol. 12. 

Loewi: Wien. klin. Woch., 1907, No. 25. 

Loewi: Arch. f. exp. Path. u. Pharm., 1908, vol. 59. 

Loewi u. Meyer: Arch. f. exp. Path. u. Pharm., 1905, vol. 53. 

Meltzer u. Auer: Am. Journ. of Physiol., 1904, vol. 11. 

Schultz, W. H.: Proc. Soc. for Exp. Biol, and Med., New York, 1908, vol. 6, p. 23. 

Wessely; Ber. d. Ophthalm. Ges., Heidelberg, 1900. 

Astringent and corrosive substances, or those which cause in- 
flammation, produce the same changes in the outer portions of the 
eye, the cornea and conjunctiva, as in other mucous membranes ; con- 
sequently, for their actions on the eye the reader may be referred 
to the chapter on the pharmacology of inflammation. 

Antiseptics. — The same holds true also for the antiseptics, of 
which the mild insoluble mercury preparations, the yellow oxide and 
the white precipitate, in the form of ointments, and calomel, in its most 
finely powdered form, as a dusting powder, are frequently employed 
in the practice of ophthalmology. 

ABRIN 
In this section it seems proper to discuss in part the action of 
abrin, a toxin, probably albuminoid in nature, which is obtained from 
the seeds of Arus precatorius, or jequirity (8. Martin, Osborne). 
Mere traces of this substance applied to the conjunctiva cause an acute, 
rapidly progressing conjunctivitis, with emigration of leucocytes and 
pronounced serous infiltration, effects which at times appear to be of 
value in the treatment of sluggish trachoma, and particularly as a 
means of causing the absorption of trachomatous opacities of the 
cornea. As is the case with many toxins of a proteid nature, an anti- 
toxin — antiabrin — may under the influence of abrin be produced in 
the organism (Elirlich), and Homer states that it is possible to mod- 
erate the intensity of a too violent abrin action in the eye by the use 
of this antitoxin. 



MIOTICS ACTING IN PERIPHERY 161 

Dionin is another drug 1 causing pronounced conjunctival chemosis 
and oedema of the lids, which consequently may be used in the same 
way and for the same indications as abrin. It is the synthetically 
prepared hydrochloride of ethyl morphine. 

Peroxin, the hydrochloride of benzyl morphine, may also be used 
for similar purposes (Uhthoff). 

BIBLIOGRAPHY 

Ehrlich: Deutsche med. Woch.. 1891. Xo. 44. 

Martin, S., and Wolfenden: Proc. Roy. Soc, London, 1889, vol. 46. 
Osborne, Mendel and Harris: Am. Journ. of Physiol., 1905, vol. 14. 
Romer: Grafe's Arch. f. Ophth., 1901, vol. 52,* p. 72. 



CHAPTER VI 

PHARMACOLOGY OF THE DIGESTION 

i. CHEMISTRY OF THE DIGESTION 

PHARMACOLOGY OF THE DIGESTIVE GLANDS 

SALIVARY SECRETIOX 

Innervation. — The chemical transformation of the food starts 

in the mouth under the influence of the secretions of the salivary 

glands, particularly the parotid, submaxillary, and sublingual glands, 

which receive their secretory innervation on the one hand from the 

superior cervical ganglion of the sympathetic and on the other from 



IViFacia&s- 







w 



Fig. 11. — Innervation of salivary glands. Red, sympathetic nerves; blue, autonomic nerves. 

cranial autonomic nerves. The autonomic fibres for the parotid gland 
pass from the auriculotemporal branch of the fifth nerve through 
Jacobson's nerve into the glossopharyngeal, and those for the sub- 
maxillary and sublingual glands from the facial nerve through the 
chorda tympani of the lingual nerve. Both types of nerves also con- 
tain vasomotor fibres for these glands, those in the sympathetic being 
vasoconstrictor while those in the autonomic nerves are vasodilator. 
162 



SALIVARY SECRETION 163 

These nerves are, therefore, in this respect antagonistic to each other. 
The secretory fibres are also in a sense antagonistic, inasmuch as their 
excitation produces in the glands electric changes of opposite character 
(Bayliss and Bradford) , and, while in both cases a secretion of saliva 
results, that resulting from the stimulation of the sympathetic nerves 
is scanty and viscid * while that following stimulation of the chorda 
is abundant and thin. 

Reflex Excitation.— The salivary secretion may be excited re- 
flexly from the cerebral cortex as a result of stimulation of the appetite, 
a fact which accounts for the common expression "My mouth waters." 
It can, however, also be induced by disgust or nausea, for stimulation 
of the vomiting centre (p. 177) also affects the centres controlling the 
salivary secretion. This secretion may also be induced by taste, smell, 
and other sensory stimuli acting upon centres which he in the subcor- 
tical regions and in the medulla. Of these the mechanical stimulus 
resulting from the act of chewing, which causes an abundant secretion, 
is especially important. 

The parotid gland is much more developed in herbivorous animals, which, 
as a rule, chew their food for a longer time and more thoroughly, than in the 
earnivora, who, as a rule, bolt their food, or in those animals which live in the 
water. In man the average amount of saliva which is secreted is very consider- 
able, amounting under the influence of chewing to as much as 500-700 gm. 
in an hour, and, as the movements of talking produce a similar effect, in 24 
hours as much as 1-2 kilograms may be secreted (Tuczek). In the horse and 
ox the amount secreted in 24 hours may exceed 40 kilograms. 

Chemical, stimuli, especially acids, bitters, and pungent sub- 
stances, such as mustard, by their action on the mucous membrane 
of the mouth, reflexly stimulate all these glands, but especially the 
submaxillary. 

DIRECT STIMULATION" 
Quantitatively the salivary secretion is directly influenced by : 

1. The composition of the blood, — i.e., the water content of the 
blood and the tissues. If this is very low, as after profuse sweating 
or diarrhoea, the secretion of saliva stops. 

Otherwise the salivary secretion is, within wide limits, independent both 
of the blood flow through the glands and of the chemical constituents of the 
blood, it being little influenced even by such substances as the iodides and 
bromides which are excreted in it. The salts of polybasic acids and sugar are 
not excreted in the saliva, and metal oxides are excreted only in the form of their 
halogen Baits (('I. Bernard). Herein is seen a fundamental difference in the 
behavior of the true glands from that of the kidneys. 

2. Substances which excite the extra- or the intra-glandidar nervous 
mechanism. The cranial autonomic organs arc stimulated by these 
drags, which in general are autonomic stimulants, pilocarpine, physo- 

* In the c:il nhuif Hi.' sympathetic saliva is poorer in ash than the chorda 
saliva (Langlry). 



164 PHARMACOLOGY OF THE DIGESTION 

stigmine, muscarine, choline, acting on the nerve-endings while nicotine 
stimulates the cells of the ganglia. 

Choline, (CH 3 ) 3 NOH C = H 4 0, is a basic substance which is widely dis- 
tributed throughout the body (Fiirth u. tichivarz, Schwarz u. Lederer, Kino- 
shita) and which forms a part of the complicated molecule of lecithin. It is 
not improbable that this substance is of considerable importance for the main- 
tenance of the normal tone of the autonomic ganglia and nervous organs, acting 
upon them perhaps much as does epinephrin on the corresponding sympathetic 
nervous organs. 

The power of tobacco, especially when chewed to increase the secre- 
tion of saliva, is a matter of common knowledge. Profuse salivation 
is often a disturbing side-effect of pilocarpine when this drug is 
employed for other purposes, but small doses (up to about 0.04 gm. 
per diem) are occasionally useful in cases of suppression of the 
salivary secretion from nervous or other cause, in which the taking 
of food has consequently been rendered difficult. 

Mercury salts may also cause a profuse flow of saliva, a very 
disturbing and undesirable and by no means infrequent occurrence 
during mercurial treatment, which is due to an action on the autonomic 
innervation, but whether centrally or peripherally is not known. 

INHIBITION 
All these autonomic stimulations of the secretion of saliva may be 
completely inhibited by atropine and its congeners, although the 
vessels in the glands are not contracted. As ptyalism — i.e., pathologi- 
cally augmented flow of saliva due to other causes, such as neuroses, 
pregnancy, helminthiasis, etc. — as a rule is also primarily due to 
autonomic stimulation, this symptom may generally be relieved by 
atropine. 

If the secretion of the submaxillary gland be stopped by a dose of atropine 
just large enough to produce this effect, it may be excited again by pilocarpine 
and once more stopped by a second dose of atropine. After this larger dose of 
atropine, however, it is hardly possible again to excite secretion by further 
administration of pilocarpine. It is thus seen that, while there is a reciprocal 
antagonism between these two drugs, the affinity of atropine for the autonomic 
nerve-endings is much stronger than that of pilocarpine, much as is the case 
with the relative affinities of carbon monoxide and oxygen for haemoglobin. 

Except in very markedly toxic doses, atropine does not affect that 
secretion of saliva which follows stimulation of the sympathetic. Such 
may be induced experimentally by the intravenous administration of 
epinephrin or inhibited by morphine, the effect of the latter being 
probably due to central action. 

The innervation of the other glands in the mouth is essentially similar to 
that of all the true salivary glands. In them, however, stimulation of the 
autonomic nerves which reach them through the facial nerve causes a more 
concentrated secretion while stimulation of the sympathetic nerves supplying 
them results in a more dilute secretion (Rethi), but to drugs they react like the 
salivary glands. 



GASTRIC SECRETION 165 

Elimination through the Salivary Glands. — The chemical com- 
position of the saliva cannot be essentially altered, but with more 
abundant flow there is a relative decrease of its organic and a relative 
increase of its inorganic constituents, particularly of the carbonates 
(Fleckseder, Binet). Only a few substances foreign to the body, 
such as hexamethylenamine {Hanzlik) and the iodides, bromides, and 
mercurial and lead compounds, are excreted by the salivary glands, 
as are also certain alkaloids, among them morphine and quinine, which, 
by their bitter taste, betray their presence in the secretion. 

BIBLIOGRAPHY 

Bayliss and Bradford: Proc. Physiol. Soc, Journ. of Phys., 1888, vol. 6, 

Bernard, CI.: Arch, gener. de med., 1853, vol. 1, p. 5. 

Binet: These de Paris, 1884. 

Fleckseder: Ztschr. f. Heilk., 1906, vol. 27; here literature. 

Fiirth u. Schwarz: Pfliiger's Arch., 1908, p. 124. 

Hanzlik, P. J.: Journ. of the A. M. A., 1910, vol. 54, p. 1940. 

Kinoshita: Pfliiger's Arch., 1910, vol. 132, p. 607. 

Langley: Journ. of Physiol., 1885, vol. 6, p. 92. 

Marino Zucco and Martini: Arch. Ital. Biol., vol. 21, 1894. 

Rethi: Sitz.-Ber. d. Akad. d. Wiss. Wien Okt., 1905, vol. 114. 

Sehwarz u. Lederer: Pfliiger's Arch., 1908, p. 124. 

Tuczek: Ztschr. f. Biol., 1876, vol. 12, p. 534. 

THE GASTRIC SECRETION 

Innervation. — The gastric secretion is both excited and inhibited 
by two sets of fibres which are brought to it in the vagus. While 
there is no proof that stimuli which can excite secretion reach this 
organ through the sympathetic nerve, by analogy with the mechanism 
of the pancreatic secretion, the behavior of which in all other par- 
ticulars resembles that of the gastric secretion, it may be assumed as 
probable that they do so. 

Chemical Stimulation and Inhibition. — The secretion of the 
gastric juice is determined normally by the chemical action of the 
stomach contents on the gastric mucous membrane, quite indepen- 
dently of this nervous mechanism, which is controlled by reflexes 
acting through the central nervous system, the extractives of meat 
(meat soup), albumoses, peptones, and bread acting as stimulants, 
while fats inhibit it. Acids increase while alkalies diminish it. 

Even this chemical action on the mucous membrane, however, is 
also the result of reflexes which occur in the nervous plexuses of the 
stomach wall and are not affected by section of both vagi. Conse- 
quently it may be concluded that they are independent of the central 
nervous system. 

Our knowledge of these and other very important facts concerning 
the secretion of gastric juice has been obtained by means of the experi- 
mental methods of Pawlow. This physiologist has devised a method 
of forming a "small stomach," by separating a portion of the fundus 
of the stomach from the rest of this organ in such a fashion 1li.it it 



166 PHARMACOLOGY OF THE DIGESTION 

forms a blind sac opening through the abdominal wall but still 
remaining connected with the large stomach by nerves and vessels and 
thus receiving all the nervous impulses which are excited locally in the 
large stomach or which originate in the central nervous system. The 
secretory activity of this small stomach gives an essentially true picture 
of that of the large stomach. 

According to Starling and Edkins, the chemical stimulation of the secre- 
tory activity of the stomach is due to the direct stimulation of the gastric 
glands by secretin, a substance formed in the mucous membrane of the pylorus 
by acid or by products of digestion. 

DIRECT ACTION OF DRUGS 

The secretion of gastric juice may be excited by pilocarpine, 
choline, etc., and also by morphine,* and may be temporarily inhib- 
ited by atropine. From a practical point of view the action of pilo- 
carpine in conditions of pathologically diminished gastric secretion is 
of no importance, for the following reasons : Such disturbance of func- 
tion results either from disease of the gastric mucous membrane 
(gastritis, carcinoma, etc.), in which stimulation through the vagus 
would produce no effect and in which only the administration of pepsin 
and HC1 could be of value, or from nervous disturbances (inhibitions), 
in which case it is often accompanied by a normal or even in- 
creased motility and compensatorily increased pancreatic secretion 
(Cohnheim), under which conditions the digestion either remains 
normal and demands no interference, or else the insufficiently digested 
ingesta rapidly pass into the intestine and cause diarrhoea, which 
would only be aggravated by the administration of drugs like pilocar- 
pine, which stimulate the vagus. In such cases assistance is rather to 
be expected from morphine, which inhibits the motility of the stomach 
and at the same time, after temporarily inhibiting the gastric secre- 
tion, increases it to a considerable extent (see p. 189). [While the 
above statement is theoretically correct, there is still much in it that is 
too hypothetical to permit the clinician to adopt such suggestions, 
particularly as the use of morphine would be extremely dangerous in 
chronic conditions of subacidity and as the acute cases almost invaria- 
bly respond satisfactorily to other methods of treatment. — Tr.] In 
this connection it should be mentioned that in chronic morphinism the 
gastric secretion gradually and progressively diminishes until it fails 
entirely, re-establishing itself again only if the habit be abandoned 
(Eitzig). 

* This has been established by Riegel in dogs with a Pawlow small stomach, 
and also under various conditions in man. On the other hand, Leubuscher and 
Schafer found after oral administration of morphine normal acid values but after 
subcutaneous administration subnormal values. The reason for these contradic- 
tory findings is not clear, but it is possible that they are due, at least in part, 
to the admixture of different amounts of the alkaline saliva (Bickel u. Pincus- 
sohn). 



GASTRIC SECRETION 167 

Reflex Stimulation by Drugs. — A sluggish and insufficient secre- 
tion may usually be stimulated in a reflex fashion by substances with 
a pronounced taste or smell and which stimulate the appetite. Among 
these may be mentioned wine, salt, spices, and pepper, as also certain 
substances which even when given by enema produce the same reflex 
effects by their action on the intestinal mucous membrane. Such are 
alcohol, ethereal oils (Wallace and Jackson), and probably many 
other substances which act as mild local irritants. 

Inhibition of Hypersecretion. — Of much greater importance is 
the relief of the so-called hyperacidity of the gastric juice, which is 
more correctly, however, a hypersecretion, for, as Pawlow has shown, 
the HC1 concentration of the secretion of the peptic glands is never 
increased above the normal. The apparent hypersecretion, however, is 
often due to nothing else than an accumulation of the continually 
secreted gastric juice, which, in cases with motor insufficiency and 
spasm of the pylorus, is not sufficiently neutralized by saliva from the 
mouth or by mucus from the stomach (Katschkowski) . In this 
connection it should be remembered that hyperacidity itself has a 
tendency to cause spasm of the pylorus. In such cases the best drugs 
to use are the alkaline carbonates, calcined magnesia, lime water, etc., 
which both inhibit the secretion and also neutralize the excess of acid. 
Lavage of the stomach is also at times indicated in these conditions. 

If as the result of motor insufficiency and of the dilatation of the 
stomach, which usually accompanies insufficiency, the contents of the 
stomach stagnate, various bacteria may multiply rapidly in the 
stomach and produce considerable quantities of lactic, butyric, and 
acetic acid. Under these conditions, although magnesia or soda will 
neutralize these acids and thus temporarily relieve the acid eructations 
and heart-burn, their use favors the proliferation of bacteria and thus 
tends to aggravate the condition. It is, therefore, a better plan to 
cleanse the stomach by lavage, with or without antiseptics (Naunyn). 
Hypersecretion associated with pyloric spasm, which is frequently 
present in cases of ulcer of the stomach and which interferes with the 
healing of the ulcers, may often be relieved by a long-continued use of 
atropine, of which y 2 to 2 mg. should be given by needle each day 
(Tabora, Schick). 

It may, moreover, be concluded that the secretion of the gastric 
jm'r, irill be diminished by all substances which mechanically diminish 
the susceptibility of the gastric mucosa to the chemical stimuli fur- 
nislud by the food. Indifferent colloids, like solutions of gum arabic 
and starch, or fine insoluble powders, such as bismuth subnitrate, 
talcum, and the like, which adhere to and cover the wall of the 
stomach, act in this fashion. [ [t is extremely unlikely that these pow- 
ders do actually adhere to and coyer Ihe wall of the stomach. — Tr.] 
Whether local anesthetics, such as cocaine, oirvanin, etc., also indi- 
rectly diminish g.-istric secretion has not vet been determined. 



168 PHARMACOLOGY OF- THE DIGESTION 

BIBLIOGRAPHY 

Bickel u. Pmcussohn: Sitz.-Ber. d. Berl. Akad. d. Wiss., 1907, Xo. 52. 

Edkins: Journ. of Physiol., 1906, vol. 34. 

Katschkowski : Pfliiger's Arch., 1901, vol. 84. 

Leubuscher u. Schaier: Deut. med. Woch., 1892, Xo. 46. 

Xaunyn: Deut. Arch. f. klin. Med., 1882. 

Paw low: Die Arb. d. Verdauungsdriisen, 1898. 

Pawlow: Ergebn. d. Physiol., 1902, vol. 1, p. 246. 

Eiegel: Ther. d. Gegenw., 1900. 

Riegel: Ztschr. f. klin. Med., 1899, Xo. 37. 

Schick: Wien. klin. Woch., 1910, Xo. 34. 

Tabora: Miinchn. med. Woch., 1908, Xo. 39. 

Wallace and Jackson: Am. Journ. of Physiol., 1903, vol. 8. 

PANCREATIC SECRETION 

As the pancreatic secretion is under the influence of the same 
autonomic and sympathetic innervation as is that of the stomach, 
its behavior under the influence of drugs is in most particulars the 
same as that of the gastric secretion, with the exception that fats cause 
a stimulation of the pancreatic secretion. 

Its secretion may be reflexly excited by stimulating the mucous 
membrane of the intestine, particularly that of the duodenum, by 
pungent substances, such as mustard, pepper, and the like ; but it may 
also be excited, independently of other nervous control, by the direct 
chemical stimulation of the terminal organs (secretory nerve-endings 
or secretory cells?) (Gottlieb). The specific chemical stimulant for 
this gland is a substance, named secretin by its discoverers, Sterling 
and Bayliss, which is formed in the mucous membrane of the small 
intestine under the influence of hydrochloric acid. Consequently, any 
hydrochloric acid which passes into the small intestine stimulates the 
secretion of the pancreatic juice and of bile, while alkalies inhibit 
them. 

That portion of the pancreatic secretion which is excited by secretin 
is not influenced by atropine and pilocarpine, but these drugs do in- 
fluence that portion of this secretion which results from the excitation 
of the vagal secretory nerve-ending in the pancreas. This is excited 
by pilocarpine and choline * and inhibited by morphine and by small 
doses of atropine. Larger (ten times larger) doses of atropine, how- 
ever, cause a profuse secretion of pancreatic juice in the dog (Wert- 
heimer-Lepage, Cohnheim u. Modrakowski) . For this latter effect no 
satisfactory explanation can be given at present, but it is perhaps due 
to a depression of the vagal inhibition of the secretion (Popielski) . 

In cases in which duboisine, a drug whose action resembles that of atropine, 
had been used repeatedly as a means of quieting insane patients, it has been 
observed that the patients lose weight markedly and become ill-nourished, a 

* Choline influences the pancreatic secretion in two different ways. Periph- 
erally it excites the vagal secretory nerve-endings and centrally it excites the 
nerves which inhibit this secretion and which pass to the pancreas in the 
vagus trunk. It therefore, in small doses, usually inhibits this secretion, and 
in large doses, after temporarily inhibiting secretion, stimulates it (Schwarz). 



PANCREATIC SECRETION 169 

result which is possibly due to the inhibition of the pancreatic secretion resulting 
from the use of this drug {Marandon de Montyel). As early as 1S63, V. Grafe 
stated that when atropine instillations were frequently repeated there resulted 
a " general irritable weakness and impairment of the power of assimilation." 

Internal Secretion. — In addition to the secretion which is poured 
out into the intestine, the pancreatic gland, in all probability, pro- 
duces an internal secretion which is carried throughout the body- 
by the blood, and which is of decisive importance in connection with 
the utilization of the carbohydrates, as well as for the normal absorp- 
tion of the fats. When this internal secretion fails, as in cases of 
pathological degeneration or experimental extirpation of the pancreas, 
severe diabetes develops and, as a rule, the absorption of fat is mark- 
edly impaired.* The oral administration of pancreas preparations 
appears in these cases to improve the absorption of fat, but produces 
no favorable effects whatever on the diabetes. Thus far we know of 
no drugs or other agents which increase or diminish or in any other 
fashion influence the internal secretion of the pancreas. 

BIBLIOGRAPHY 

Cohnheim u. Modrakowski: Z. f. physiol. Chem., 1911, vol. 71, p. 273. 

Fleckseder: Arch. f. exp. Path. u. Pharm., 1908, vol. 59, p. 407. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1894, vol. 33. 

v. Grafe: Griife's Arch., 1803, vol. 9, Part 2, p. 71. 

Lombroso: Pfiiiger's Arch., vol. 112, 1906. 

Lombroso: Arch. f. exp. Path. u. Pharm., 1907, vol. 56, p. 357. 

Marandon de Montyel: Bull, de Ther., 1894, vol. 63. 

Modrakowski: Pfluger's Arch., 1906, vol. 114. 

Popielski: Zentralbl. f. Phvs., 1896. 

Schwarz, C.: Zentralbl. f. Physiol., 1910, vol. 23, No. 11. 

.Starling and Bayliss: Journ. of Physiol., 1902, vol. 28, p. 325. 

Wcrtliuimer-Lepage: Ue Taction de quelques alcaloides, etc., Lille, 1904. 

THE SECRETION OF THE BILE 

The secretion of bile is controlled by the same nervous and chemi- 
st I influences as is that of the pancreas. Under the influence of 
the ingestion of food these two secretions run along almost exactly 
parallel (see Fig. 12), both being stimulated by secretin. The expul- 
sion of the bile from the gall-bladder is accelerated by drugs which 
stimulate the vagus and inhibited by those which stimulate the sympa- 
thetic. 

I'lnlcr the influence of pilocarpine the gall-bladder contracts and the 
sphincter of the ductus choledochua closes, but a little later relaxes completely. 
I in. pi in-, on the other hand, causes a relaxation of the gall-bladder and of 
this Bphincter (Doyon), an action which is therapeutically of importance in con- 
nection with gall-atone colic, which probably is produced by contraction of the 
bladder and not by that of the duet f Aschoff) . 

•Thifl is not always the case, however, for when the pathological condition 
develops slowly the absorption of the fat may remain normal or after temporary 
impairment may become normal again [Fleckseder, J^ombroso). 



170 PHARMACOLOGY OF THE DIGESTION 

Chologogues. — Of particular importance to the physician is the 
question "whether or not there are any drugs or other means of 
appreciably increasing- the secretion of bile without producing other 
undesirable effects. 

The drugs of the pilocarpine group are not suitable for this pur- 
pose, as they affect all the organs of the autonomic system. Further, 
they simply cause the bile to flow out of the gall-bladder more rapidly 
■without augmenting its secretion by the liver. However, certain sub- 
stances are known to be specific stimulants of this secretion. These 
are bile itself or the salts of the biliary acids, soaps, albumoses, dilute 
HCl (Weinberg) and to a lesser degree the benzoate and the salicy- 
lates of soda. Neither soda nor Glauber's salt or other cathartics pro- 
duce any demonstrable increase in the secretion of bile, while calomel 
in cathartic doses actually inhibits it (Prevost and Binet, Boy on and 
Dufourt). 

Gall-stone patients are commonly advised, often with benefit, to use 
Carlsbad salts or sodium oleate (under various trade names) or various 
mixtures of cathartics. (One popular one, chologen, contains calomel, podo- 







Fia. 12. — Secretion after taking food: a, pancreatic secretion after milk; b, after meat; 
c, after bread; ai, gastric secretion after milk; 61, after meat; ci, after bread. 

phyllin, and an ethereal oil.) It is difficult to determine whether these drugs 
are actually curative or not. Probably the benefit which often follows their use 
is chiefly due to their power of curing or relieving the inflamed and irritable 
condition of the mucous membrane of the gall-bladder, which renders it tender 
and causes spasmodic contractions of the gall-bladder, by which gall-stones, 
which may be present without causing symptoms, are forced into the duct, 
causing colic and obstructive jaundice. In this connection, it is to be remem- 
bered that chronic inflammation of the mucous membrane of the gall-bladder 
is always a necessary preliminary condition for the production of the gall-stones 
themselves (lit., Naunyn, Herter). It is difficult to imagine in what manner 
Carlsbad salts can exert any favorable effects on the mucous membrane of the 
gall-bladder, for probably neither the neutral salts nor the carbonates are 
excreted in the bile. 

Elimination and Antisepsis. — Different drugs and poisons are secreted 
by the bile, among others Cu, Pb, Hg (Langer), amyl alcohol, methylene blue 
(Bra tier), menthol (R. Stern), and hexamethylenamine (Crowe). Of the last 
two, when administered in sufficient doses (of menthol 6.0 gm., of hexamethyl- 
enamine 5.0 gm. per diem), enough is secreted to sterilize the bile. 



SECRETION OF BILE 171 

"When the bile is prevented from joining the pancreatic juice in the 
intestine, this latter cannot by itself properly prepare the fats for 
absorption, so that the stools contain large amounts of fat. It is 
quite remarkable that under these conditions the administration of 
bile with the food is of no benefit. Apparently the pancreatic juice 
and the bile must be very thoroughly mixed together and in exactly 
correct proportions in order that this function shall be properly 
performed, and apparently such a mixing cannot be attained 
artificially. 

Other Liver Functions. — The manufacture of bile is only one 
of the many functions of the liver, which is an organ in which analytic 
and synthetic reactions of most varying nature take place. Among 
these functions one of the most important is that of transforming the 
carbohydrates into glycogen and storing them up as such, and of form- 
ing and supplying glucose to the body as it is needed. How these 
two chemical processes are controlled is unknown, but it is very- 
probable that the formation of glycogen is accomplished with the aid 
of the internal secretion of the pancreas, and that the transformation 
of glycogen into glucose takes place under the influence of epinephrin, 
the internal secretion of the suprarenals. 

Other chemical functions of the liver, such as the anabolism of 
fats and proteids, are probably markedly influenced by the internal 
secretion of the thyroid, iodothyrin, but concerning this we know com- 
paratively little. From all that is known, however, it appears that, in 
contrast to the function of the true glands, the activity of the liver is 
regulated not by secretory nerve impulses but by chemical stimuli, 
which are supplied by specific substances, Starling's hormones, and 
also by the composition and amount of the blood supply. 

BIBLIOGRAPHY 
Aselioff: Verh. d. Path. Ges., 190G. 

Brauer: Ztschr. f. physiol. Chem., 1904, vol. 40, p. 182. 
Crowe, J.: The Johns Hopkins Hosp. Bull., 1908, vol. 19, No. 205. 
Doyon et Dufourt: Arch. d. Phys., 1897. 
Dovon: Etude analytique, etc., Lyon, 1893. 
Berter: Trans, of the Congr. of Am. Phys., 1903, vol. 0. 
Langer: Ztschr. f. exp. Pathol, u. Ther., 190G, vol. 3. 
Xamiyii : Cholelithiasis. 

Paw low: Das Experiment, YYieshaden, 1900, p. 13. 
Prfivost et Binet: Compt. rend., 1888, 10G. 

Stern, I:.: Ztschr. f. Hygiene u. lnf.-Krankh., 1908, vol. 59, p. 129. 
Weinberg: Zbl. ges. Physiol, u. Pathol, d. Stoffw. N. F., 6, No. 1. 

THE SECRETION OF THE INTESTINAL JUICE 

The secretion of the intestinal juice — the chief constituents of 
which are, in the duodenum, the ferment, enterokinase, which activates 
trypsin, and, in the jejunum, invertase and erepsin, which possesses 
the power of decomposing the albumoses — is excited by local, mechani- 
cal, or chemical stimulation of the intestinal mucous membrane, par- 



172 PHARMACOLOGY OF THE DIGESTION 

ticularly by the pancreatic juice and by the ingesta. Up to the present, 
the extent to which the central nervous system controls this secretion 
has not been sufficiently investigated, and the same is true as regards 
the action of drugs. Consequently, we know little of the manner in 
which this secretion may be affected by pharmacological agents. 

The mucous glands, which are present throughout the whole 
extent of the alimentary tract, are stimulated to secretion by the alka- 
line carbonates and are inhibited by acids and astringents. These 
latter drugs also precipitate and render insoluble proteid substances 
dissolved or suspended in the fluid contents of the intestine, and 
consequently they increase the consistency of the intestinal contents 
and render them drier. 

Elimination through the Intestine. — As has already been men- 
tioned in connection with the secretion of saliva and of bile, various 
substances for which the body has no further use, such as Ca, Fe, 
phosphoric acid, and organic detritus and various foreign substances, 
are eliminated in the different digestive juices. It is thus apparent 
that the mucous membranes of the stomach and intestine are organs 
of excretion, a fact which is of particular importance in connection 
with certain poisons. Thus, compounds of the heavy metals, Pb, Cu, 
Hg, Bi, Fe, and Mn, and arsenic and antimony and the halogen salts 
of the alkalies, are excreted in this fashion, as are also morphine in 
considerable extent and, to a less degree, other alkaloids and the 
drastic cathartics, aloin and podophyllin, as also bacterial toxins and 
snake venom. The harmful actions on the intestine which result 
from the administration of many of these substances, even when 
administered subcutaneously or intravenously, is due to their excretion 
by this route. 

ABSORPTION IN THE ALIMENTARY CANAL 

IX THE STOMACH 

Absorption occurs throughout the whole intestine, starting in the 
duodenum and ending in the rectum. With the exception of those 
substances which are soluble in the lipoids, the mucous membrane of 
the mouth and of the stomach does not absorb mentionable amounts 
either of water or of food-stuffs or other substances in aqueous 
solution (Karmel, Meltzer). Lipoid soluble substances readily pene- 
trate the epithelial covering and more or less rapidly enter the 
blood, so that it is possible that such substances as nicotine or phenol 
may be quite readily absorbed by the mucous membrane of the 
mouth in amounts sufficient to cause a systemic poisoning. The 
slight power of the stomach to absorb substances which are not soluble 
in the lipoids — for example, most salts of the organic and inorganic 
bases — may be of pharmacological importance in cases with motor 
insufficiency of the stomach, as a result of which the gastric contents 



ABSORPTION IN STOMACH 173 

remain for many hours in the fundus of the stomach, for under such 
conditions the expected effects from medicines administered by mouth 
may not occur or may at least be very markedly retarded. The same 
result must naturally ensue if the motor activity of the stomach has 
been inhibited by such drugs as morphine or epinephrin, in which 
case the gastric contents do not pass on into the duodenum, in which, 
as already stated, absorption really begins. 

Acceleration of Absorption. — If the lipoid structure of the 
superficial layer of the mucous membrane be loosened or softened, 
water and salts, sugar, peptones, etc., in solution are able to pass 
into it more readily, and consequently may be absorbed. This is appar- 
ently the explanation for the fact that fluids' containing alcohol or 
carbonic acid and substances dissolved in them are absorbed from the 
stomach, although only in small quantities (v. Tappeiner, Hirsch, 
v. Mering). According to Brandt, pungent irritating substances like 
oil of mustard or of peppermint, or pepper, increase absorption. As 
this is not due to the hyperemia as such, which is caused by them, 
it must be due to a chemical change in the cells, a cytolytic action, 
altering their permeability. 

Bitters do not directly favor absorption from the stomach, although 
they cause hyperemia of the mucous membrane, but when taken an 
hour before eating it is claimed that they do so (Jocllbauer) . In dogs 
large doses, more especially if repeatedly administered during a con- 
siderable period, apparently retard the emptying of the stomach and 
consequently also retard the absorption of the food from the intestine, 
but small doses apparently accelerate both these processes (Heubner). 

Retardation of Absorption. — Mucilaginous substances, such as 
gum arabic, starch, and pectin, markedly diminish the resorptive 
power of the stomach (Brandt). 

ABSORPTION IN THE INTESTINE 
The intestinal mucous membrane absorbs not only lipoid soluble 
substances, but also those insoluble in the lipoids yet soluble in water. 
Most, but not all, of the effective forces to which this absorption is due 
an- known to us, and are diffusion and osmosis on the one hand and 
nitration pressure on the other. The latter is apparently of sub- 
ordinate importance, and is furnished partly by the pressure of the 
muscle of the intestinal wall and partly by the pumping action of 
the muscles of the villi. Contraction of the intestinal vessels retards, 
and dilatation accelerates absorption (Sollmann, Ilanzlik and Pitcher). 
in very general terms it may be stated that lipoid soluble substances 
are incomparably more readily and rapidly absorbed than those insolu- 
• '1 ( ' in the lipoids, and in general in direct proportion to this solubility. 

Hdber, by his very ingenious experiments, has shown that very probably 
the path of absorption for substances which are insoluble in lipoids lies be- 
tween the cells, bul for those Boluble in lipoids through the cells themselves, 



174 PHARMACOLOGY OF THE DIGESTION 

the absorption occurring in the former instance intercellularly, in the latter 
intracellularly. 

It has not been definitely established just how the fats, which are insoluble 
in water, are absorbed, but it is probable that they are first saponified or else, 
like the fat in the blood-serum, are rendered soluble by chemical union with 
lecithin and proteids (Mieschcr) . However, recent observations (W. Croner) 
indicate that in the dog a large portion of the fat is absorbed from the small 
intestine in a state of emulsification and is not first saponified, and that larger 
portions are absorbed in the lower than in the upper segment, while the 
absorption of the saponified portion occurs only in the lower segment. After 
absorption the fats pass into the intestinal lymphatics and mesenteric veins. 

Cod-liver oil enjoys a peculiar reputation as a food and as a 
curative agent. To it have been attributed, partly because of the 
presence in it of an inconstant and very small amount of iodine or of 
certain basic substances (aselline, etc.), curative properties in tuber- 
culosis, scrofula, rickets, and other diseases. Certainly established 
in regard to it are the two facts, that it is more readily and per- 
manently emulsified than other fats, a property not due entirely to its 
containing free fatty acids, and that it, especially before purification, 
is much better absorbed from the intestine than other fats (Gad, 
Marpmann, Naumann, Croner). 

These properties are sufficient to explain its value as a very efficient, 
because very digestible, means of improving digestion, but are not 
sufficient to explain its other real or fancied curative properties. As 
is well known, cod-liver oil, even the official purified oil, has a most 
repulsive taste, which cannot be entirely corrected by the addition 
of flavoring agents. Perhaps impregnation with carbonic acid is the 
best manner of securing this. Lipanin (pure olive oil with 6 per cent, 
oleic acid), recommended as an agreeably tasting substitute, is utilized 
much more poorly than cod-liver oil and even than pure olive oil. 

The saturated non-volatile hydrocarbons, the paraffins, which can in no 
way be brought into solution in water, are not absorbed from the alimentary 
canal. 

ABSORPTION OF SALTS 

The rate of absorption of the lipoid insoluble substances, such as 
the inorganic and organic salts, the sugars, amido acids, etc., in 
general runs parallel with their rate of diffusion. With isotonic 
and slightly hypertonic solutions of neutral salts, the rate of absorp- 
tion increases with their anions as follows : HP0 4 < S0 4 < N0 3 < Br < CI, 
and with their kations, Mg<Ca<Na<K, and exactly the same order 
holds good for their observed rates of diffusion. With the salts 
of organic acids also the rates of absorption are found to vary pro- 
portionately to their diffusibility, but here their lipoid solubility in- 
fluences their absorbability to some extent (Hober). 

In general it may be stated that the salts of sodium, potassium, 
and ammonium with monobasic acids are readily diffusible and absorb- 
able, while those with the polybasic acids diffuse slowly and are also 



ABSORPTION FROM INTESTINE 175 

absorbed with difficulty ( Wallace and Cusliny) .* The same parallelism 
holds good in general for non-electrolytes, such as the various sugars 
and amino-aeids, but salts, such as the fluorides or oxalates or the salts 
of barium, the anions or kations of which are toxic to the intestinal 
epithelium, behave quite differently, being absorbed much more slowly 
than would be expected from their diffusibility. The permeability 
and resorptive power of the intestinal mucous membrane may be very 
markedly impaired by the toxic action of other substances {Scanzoni) , 
but no one has thus far investigated whether this be due to a chemical 
alteration of the colloid membrane formed by the epithelial lining 
or to the paralysis of the active physiological factors such as the 
muscles of the villi. As this can be properly discussed only after 
discussion of the mechanism of the digestive processes, it will be 
taken up later, as will the pharmacological significance of absorption 
in the intestine in the section on cathartics. 

As the blood from the whole of the small intestine and of the colon 
passes through the portal vein into the liver, while the rectum is 
drained by the hemorrhoidal plexus, from the middle portion of which 
the blood passes directly into the general circulation, it is not a matter 
of indifference from which portion of the alimentary canal food or 
drugs are absorbed. This is the reason why powerful poisons, such as 
morphine, strychnine, and particularly carbolic acid, when adminis- 
tered by rectum may under certain conditions cause more rapid or 
pronounced poisoning than when they are introduced into the stomach, 
in which case they must first pass through the liver and only gradually 
enter the general circulation, particularly as the poisonous effects of 
most toxic substances are markedly lessened by passage through the 
liver, partly as a result of being chemically changed by conjugation 
with sulphuric acid, etc., and partly as a result of absorption and 
consequent retarded entrance into the general circulation (see Curare, 
Potassium Salts, etc., and also Rothberger u. Winterberg) . 

BIBLIOGRAPHY 

Brandl: Ztsehr. f. Biol., 1883, vol. 29. 

Croner, \Y. : I'.iochem. Ztsehr., 1009, vol. 23, p. 97. 

(■■<■] : Arch. f. Physiol., 1878, p. 181. 

Benbner: Therap. Monatshefte, 1909, No. G. 

II"I"t: Hdb. d. physik. Chem. u. Med., von Koranyi u. Richter, 1907. 

Joanovic/. it. E. Pick: W'ion. klin. Woch., 1910, No. 1G. 

Jodlbauer: Arch, intern, de Pharmacodyn., 1902, vol. 10. 

Karniel: Diss. Dorpat, 1873. 

Marpmann: MUnchn. med. Woch., 1888, p. 485. 

Meltzer: Am. Journ. Med. Sc, 1889. 

v. Mering: Verh. <!. Hongr. t. inn. .Med., 1894. 

•These authors have called attention to another parallelism in connection 
with these .suhstances. The anions of the easily absorbed salts form readily 
soluble salts with calcium, while Ihosc of the salts which are absorbed slowly 
form insoluble calcium salts. Tins, however, does not hold good for all cases. 
for potassium ferrocyanide is slowly absorbed although calcium ferrocyanide 
is readily soluble in water. 



17G PHARMACOLOGY OF THE DIGESTION 

Mieseher: Arb., vol. 1, p. 321, 1897. 

Naumann: Arch. d. Heilk., 1865, vol. 6, p. 536. 

Rothberger u. Winterberg: Arch, intern, de Pharmacodyn., 1905, vol. 15; here 

compl. literature. 
Scanzoni: Ztschr. f. Biol., 1896. 
Sollmann, T., Hanzlik u. Pilcher: Journ. of Pharm. and Exp. Ther., 1910, vol. 1, 

p. 409. 
v. Tappeiner: Ztschr. f. kl. Med., 1893. 
Wallace u. Cushny: Pfliiger's Arch., 1899, vol. 77, p. 202. 
"Wallace u. Cushny: Amer. Journ. Physiol., 1898, vol. 1, p. 411. 

II. THE MECHANICS OF DIGESTION 
DEGLUTITION 

The first of these are mastication and deglutition, which latter may 
be voluntarily inaugurated by pressing the root of the tongue against 
the palate, but which when once started is reflexly completed even 
against the will, the peristaltic action of the oesophagus pushing its 
contents downward and the cardia opening to permit their entrance 
into the stomach. The chief nervous centre presiding over this act 
lies in the medulla, and receives its afferent impulses from definite 
portions of the throat, the so-called swallowing points, which are 
specifically innervated by sensory nerves derived from the trigeminal, 
superior laryngeal, and glossopharyngeal nerves, and which are stimu- 
lated by contact with fluids or solids. 

Pharmacological Interference with Deglutition. — If these 
points are benumbed by the application of cocaine, such stimulation 
no longer causes swallowing, an effect which at times may be desirable 
during operations on the pharynx or larynx. During general anaes- 
thesia or in deep morphine narcosis, this centre becomes so unexcitable 
that stimulation of it results in swallowing movements only in the 
muscles of the pharynx but not in those of the oesophagus or cardia 
(Mcltzer)* This should be remembered when treating narcotized 
individuals; for liquids administered to them should not be simply 
poured into the mouth, but should be introduced into the stomach 
through the stomach-tube. In general anaesthesia the secretion of 
saliva should either be suppressed by such drugs as atropine or scopo- 
lamine or care should be taken to remove it from the throat, for the 
abolition of the swallowing reflex leaves the glottis open, so that the 
saliva may flow into the lungs and cause an inhalation pneumonia. 

Deglutition may also be completely or partially prevented by 
paralysis of the motor nerves in some or all of the muscles of deglu- 
tition. Pharmacologically such paralysis may be caused by drugs with 
a curare action, which paralyze the striped muscle in the upper por- 
tion of the oesophagus, or by autonomic paralyzants like atropine, 
which prevent the action of the smooth muscles of the lower oesophagus 

* Am. Journ. of Physiol., 1899, vol. 2, p. 266. 



EMESIS 177 

and of the cardia. This is of significance in connection with the 
symptoms of belladonna poisoning. This action of atropine would 
also justify its employment to relax oesophageal or cardial spasm. 

MOVEMENTS OF THE STOMACH 

In the muscular movements of the stomach one may distinguish 
peristaltic and antiperistaltic movements, which latter occur during 
vomiting, a discussion of which follows: 

Vomiting, like swallowing, is a reflex phenomenon in which numer- 
ous smooth and striped muscles cooperate together in an orderly fash- 
ion. The pylorus being closed, the contraction of the antrum of the 
pylorus drives the stomach contents into the fundus, which, previously 
and independently of its fulness, actively dilates as a result of relaxa- 
tion of its tone {Frantzen). At the same time the cardia opens, so that 
the spasmodic contraction of the diaphragm, of all the abdominal 
muscles, and also of the muscles of the fundus, all starting at the same 
time, expel the stomach contents through the oesophagus and pharynx. 
The coordination of these various acts is controlled by a centre lying 
in the medulla, the so-called vomiting or emetic centre. 

Emetic Centre. — A region has been discovered by Thumas in the lower 
layers of the medulla below the calamus scriptorius, electric, mechanical, or 
specific stimulation of which induces vomiting. This appears to be a coordinat- 
ing centre, under whose influence the centres for the innervation of the cardia and 
of the stomach, which lie in the caudate nucleus and in the region of the corpora 
quadrigemina (Hlasko), and the reflex centres controlling the abdominal respira- 
tory muscles, which are also involved in vomiting, are excited to a general 
coordinated action. Elimination of one of these centres — as occurs, for example, 
if the corpora quadrigemina be destroyed (Hlasko), or if the respiratory centre 
be inhibited by apncea (Grimm, Grewe) — prevents successful vomiting, as does 
also the prevention of the reflex by which the cardia is opened. According to 
Volenti, the opening of the cardia in vomiting may be brought about only reflexly 
as a result of the gastric and oesophageal movements, and never directly by central 
action. The centripetal fibres for this reflex run in the glossopharyngeal and 
vagus nerves, and may, at least in the dog, be so effectively put out of function 
by cocainization of the pharynx and upper oesophagus that the stomach is not 
emptied, in spite of all the other movements of vomiting. 

The vomiting centre may be directly stimulated mechanically as by the 
pressure of tumors or meningeal inflammation, or chemically as in uraemia, 
OT by various drugs or poisons, or by disturbances of the circulation in the 
brain. It may also be stimulated indirectly or reflexly by various stimuli, 
among which are psychical ones, such as disgust, or by labyrinthine disturbances, 
or by irritation of the pharynx or of abdominal organs. The centripetal impulses 
from the abdominal organs to the medullary vomiting centre pass upward in 
the vagi, for, after their division, vomiting can no longer be induced by influences 
acting on the stomach or intestine. 

The Bolipedes, ruminators, rodents, and chiroptera (bats) cannot vomit, 
as they do not possess tin' necessary coordinating mechanism. If the pathologi- 
cally dilated fundus be overfilled, vomiting is generally difficult, but in the less 
developed fundus of small children it is facilitated, because simple contraction of 
the antrum of the pylorus unassisted by the pressure of the abdominal muscles 
is sufficient for the expulsion of the stomach contents because the tone of the 
cardia is so weak [Volenti). 

12 



178 PHARMACOLOGY OF THE DIGESTION 

Narcosis of the Emetic Centre. — In deep narcosis, such as that 
caused by morphine, chloral, etc., the vomiting mechanism does not 
act (Harnack), and consequently under such conditions the emptying 
of the stomach may often be attained only by the use of the stomach- 
tube. 

BIBLIOGRAPHY 

Grewe: Berl. klin. Woch., 1874. 

Grimm: Pfliiger's Arch., 1871, vol. 4. 

Hlasko: Diss., Dorpat, 1887. 

Thumas: Virchow's Arch., vol. 123, 1891. 

Valenti: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 119. 

EMETICS 

All substances which, by their powerful action on the mucous 
membrane of the stomach or intestine, cause irritation, inflammation, 
or corrosion, may cause vomiting. Consequently, vomiting is a very 
common symptom in almost all poisonings, and thus forms one of 
the most important reactions by which the organism protects itself. 
As emetics in the more limited pharmacological sense, however, we 
speak of and use only substances which cause vomiting as their 
primary effect without, for the time being, appreciably affecting other 
organs than those which participate in the act of vomiting. One can 
differentiate between 

1. Direct emetics, which excite the vomiting centre directly, and 

2. Reflex emetics, which act by irritating those specific sensory 
nerve-endings, in the mucous membrane of the stomach and intestine, 
the excitation of which induces vomiting. 

We are forced to assume the presence in the intestinal mucous membrane 
of specific " emetico-sensory " nerve-endings, because these react to certain 
stimuli such as marked distention and to certain chemical reagents, but not to 
other even violent stimuli which cause pain or excite secretion or normal peri- 
staltic movements. As is well known, a similar differentiation is found in the 
cutaneous nerve-endings through which stimuli are excited. 

Vomiting, however induced, is always, except in small children, 
preceded by a prodromal stage of nausea, which is accompanied by 
pallor, cold sweats, increased secretion from the salivary glands and 
from the nasal and bronchial mucous membranes. A feeling of nausea 
and often marked muscular weakness develops, and at the same time 
the pulse becomes somewhat weaker and more rapid and the breathing 
rapid and irregular. As a rule, after the stomach has been emptied 
and vomiting has ceased, all these symptoms disappear, except that 
traces of the muscular weakness remain (Ackermann). It is thus 
apparent that stimulation of the vomiting centre, even before it has 
attained the threshold value for emesis, causes an accompanying excita- 
tion of a whole group of phenomena, among which the inhibition of 
voluntary movement is particularly remarkable, and at times is so 
extreme that it completely paralyzes and renders apathetic the affected 



CENTRALLY ACTING EMETICS 179 

individual so that his condition resembles that of severe shock 

{Harnack) . 

The slight degrees of nausea, which express themselves only in aug- 
mentation of the secretions and perhaps in a diminution of the tone 
of the bronchial muscles, are utilized therapeutically to facilitate the 
expectoration of tenacious mucus from the bronchi. In this ivay the 
emetics in non-emetic doses may act as expectorants (see p. 343 ff.). 

CEXTRAELY ACTING OR DIRECT EMETICS 
Apomorphine. — The hydrochlorate of apomorphine, a base obtained 
by allowing mineral acids to act upon morphine (Mathiesen u. 
Wright), when injected subcutaneously in doses of 5-10 mg.,* after 
5-10 minutes, causes nausea and vomiting, which is repeated two or 
three times, after which the patient completely recovers from these 
symptoms. If larger amounts be administered, the vomiting occurs 
repeatedly for an hour or longer, and is followed by a condition of 
moderate weakness and somnolence which usually soon passes off. 
When taken by mouth, apomorphine acts much less energetically, 10-20 
times as large a dose being necessary and the vomiting occurring only 
after half an hour or even later. From this it may be concluded 
that the vomiting caused by apomorphine is not induced reflexly from 
the mucous membrane of the stomach and intestine, but results from 
direct action on the vomiting centre after the drug has been carried 
there in the blood. 

This is in accordance with the fact that even after section of both vagi, 
in which lie the centripetal nerves running from the stomach and intestine to the 
vomiting centre, apomorphine causes nausea and coordinated vomiting move- 
ments, which, however, on account of the disturbance in the motor innervation 
of the stomach, do not always actually cause emesis (Greive). There is no 
ground for the assumption that apomorphine also excites antiperistaltic move- 
ments of the stomach by direct excitation of the autonomic centres in or near 
the stomach. The phenomena observed by Schiitz in stomachs removed from 
dogs previously poisoned by apomorphine or other emetics, which have been 
held to speak for this assumption, are to be looked upon as merely typical 
reversed peristalsis occurring occasionally, which, even without the influence 
of any drug, may also be caused by anaemia of the stomach and which were 
repeatedly observed by Kchtitz himself in the unpoisoned isolated stomach 
( Frantzen ) . 

As has already been mentioned, stimulation of the vomiting centre, 
even when vomiting does not occur, induces associatively the symptom 
complex of nausea, and if this centre is directly excited by chemical 
means — as,' for example, by apomorphine — or as a result of cerebral 
anopmia, it is clear that this associative accompanying nausea may 
bo more pronounced and persistent than when the centre is temporarily 
excited by reflexes from the stomach or intestine 

* Tn dogs as small doses as 1.0-2.0 mp. are effective, but in cats 10.0-30.0 mg. 
must be <rivon, and in many of these animals apomorphine is entirely unable to 
induce vomiting. 



180 PHARMACOLOGY OF THE DIGESTION 

Vomiting entirely fails to occur or is only partially accomplished if one 
of the coordinating mechanisms involved in the act, perhaps that in the corpora 
quadrigemina, for some reason fails to act. In such case nausea can persist for 
a long time and be in the highest degree a source of suffering, and the motor 
inhibition and helplessness, particularly after large but ineffective doses of 
apomorphine, may be very alarming. In rather exceptional cases such a condi- 
tion may persist with unabated severity for some time even after vomiting has 
occurred (Harnack), but in such cases this is not succeeded by other harmful 
results. Even infants of but a few months old can support without harm injec- 
tions of %-1.0 mg. of apomorphine (Jurasz). Habituation does not follow its 
repeated administration, Siebert having for 4 weeks injected a dog each day 
with y 2 -2.0 mg. of apomorphine, each injection being followed after about three 
minutes by vomiting. However, many commercial preparations of apomorphine 
are contaminated by a percentage of chloromorphid, a toxic respiratory depres- 
sant, which is probably the explanation for some of the cases of poisoning which 
have followed the medicinal administration of apomorphine (Harnack u. 
Hildcbrandt) , 

Other Actions. — The vomiting centre and its coordinately controlled 
central mechanisms form the predilective, but not the only point on 
which apomorphine acts. 

In dogs in large doses (0.06-0.1 gm.), and in cats even in emetic doses 
(0.02-0.05 gm.), it causes a condition of marked excitement and confusion, with 
accelerated respiration and active forced movements. In rabbits and guinea- 
pigs also its administration is followed by great restlessness and timidity and 
an irresistible tendency to gnawing, and after doses of more than 10 mg. con- 
vulsions resulting in death occur. Hogs, which normally can vomit, cannot be 
caused to vomit by apomorphine, but- after the subcutaneous injection of 0.02- 
0.5 mg. they become highly excited and gnaw and bore in the floor and walls 
of their pens. Similar remarkable symptoms of excitement, an irresistible desire 
to lick and gnaw, are also produced by apomorphine in cattle and horses, and 
even chickens and doves -are rendered restless by it and peck continually on 
the floor and at their own claws but do not vomit (Feser). 

Other Central Emetics. — Many other substances directly stimu- 
late the vomiting and the respiratory centres in a manner similar 
to apomorphine. Their actions, however, are not so elective, but ex- 
tend usually to other functions, and consequently they are not suit- 
able for the isolated induction of emesis. In this group belong aspi- 
dosamine, an alkaloid of the quebracho bark (Harnack u. Hoffmann), 
and lobeline, an alkaloid of Lobelia inflata, which formerly was used 
as an emetic, but now is used only in small non-emetic and safe doses 
in the treatment of asthma (seep. 345). Probably veratrine, the active 
principle of Veratrum sabadilla and Veratrum viride, should also be 
placed in this group, for in addition to many other characteristic 
actions, particularly on striped muscles, it causes vomiting by a 
central action. Administered subcutaneously it is a very effective 
emetic in hogs and for this purpose it is used by veterinarians. 

Morphine also, by a probably direct action on the vomiting centre, 
induces vomiting in dogs and, as a late effect, quite often in man. 

BIBLIOGRAPHY 

Ackermann: Beob. iiber einige physiol. Wirkungen d. Emetica, Rostock, 1856. 
Feser: Ztschr. f. pr. Veteriniirwiss, 1873-75. 
Frantzen: Diss., Dorpat, 1887. 



PERIPHERAL EMETICS 181 

Grewe: Diss., Dorpat, 1874. 

Grewe: Berl. klin. Woch., 1874, vol. 11. 

Harnack: Miinchn. med. Woch., 1908, No. 36. 

Harnack u. Hildebraudt: Miinchn. med. Woch., 1910, Nos. 1 and 33. 

Harnack u. Hildebrandt: Arch. f. exp. Path. u. Pharm., 1911, vol. 65, p. 38. 

Harnack u. Hoffmann: Ztschr. f. klin. Med., 1885, vol. 8. 

Jurasz: Deut. Arch. f. klin. Med., 1875, vol. 16. 

Mathiesen u. Wright: Liebig's Ann. Suppl., 1869, vol. 7. 

Schiitz: Arch. f. exp. Path. u. Pharm., 1886, vol. 21. 

Siebert: Diss., Dorpat, 1871. 

EMETICS ACTING PERIPHERALLY OR REFLEXLY 
Ipecac, Radix ipecacuanha?, contains about 2 per cent, of a mixture 
of the alkaloids, emetine and cephaeline, and also an acid resembling 
tannin. While both of these alkaloids are emetics and cephaeline is 
the more powerful one, only emetine has been exactly studied pharma- 
cologically. It possesses a bitter and irritating taste and violently 
irritates the mucous membranes, causing in them inflammation with 
paralysis of the capillaries. Consequently, when administered in suffi- 
cient amounts, it causes in animals not only vomiting but also violent 
and at times bloody diarrhoea resembling that caused by colchicine and 
arsenical or antimonial compounds, to the effects of which emetine 
poisoning in many particulars corresponds exactly. 

As the emetic effects occur no more rapidly and are not produced by 
smaller amounts when this drug is injected subcutaneously or intravenously than 
when it is introduced into the stomach, it may be concluded that it acts reflexly 
on the gastric mucous membrane. The fact that, even after subcutaneous injec- 
tion, it reaches the gastric and intestinal mucous membrane is evidenced by the 
inflammation of the intestinal mucous membrane and by the identification of 
emetine in the intestinal contents (D'Ornellas). 

On the other hand, Thumas states that a solution of emetine applied 
directly to the vomiting centre in the medulla quickly induces vomiting, and 
consequently he looks upon it as an emetic which acts directly on this centre. 
However, in view of the general irritating effects of emetine, his results permit 
of more than one interpretation. After elimination of the centripetal vagus 
fibres, vomiting was not caused by it in Duckworth's and Polichromie's experi- 
ments, while in those of D'Ornellas they occurred in some cases but only very 
late and to a very slight extent. 

These observations indicate that it acts reflexly and not directly. 

In man 10.0-15.0 mg. of emetine cause nausea and after %-l hour 
vomiting, but, on account of the difficulty with which this drug may 
be preserved, it is not suitable for general use at the present. As 
galenic preparations of ipecac contain the emetine only in colloidal 
combination, they never cause marked irritation of the intestine,* but, 
as should be expected from their very slow absorption, only persistent 
nausea, and after a sufficient dose (for adults 1.0-2.0 gm.) vomiting 

* [The largo doses employed in the treatment of dysentery not infre- 
quently cause considerable irritation of the intestinal mucous membrane, and 
consequently may aggravate or cause dysenteric symptoms, a fact which should 
mil be forgotten when the drug is employed in such cases, otherwise its adminis- 
tration may at times be continued after it has accomplished the desired effect on 
the uma-ba?. — Tu.l 



182 PHARMACOLOGY OF THE DIGESTION 

in the course of %— 1 hour. On account of its slow action, ipecac is 
not much used as an emetic but chiefly as an expectorant. 

In its original home this drug has been employed for centuries 
not only as an emetic but also as a specific in dysentery, being used for 
this purpose in the form of a concentrated decoction.* After repeated 
doses it ceases to cause vomiting and its curative action in the intestine 
manifests itself. Probably the effective factor in these cases is essen- 
tially the astringent ipecacuaha-tannic acid (see Astringents) .t Conse- 
quently "emetine-free" ipecac preparations have been prepared and 
recommended for the treatment of dysentery, but it is doubtful whether 
these possess any advantage over any other preparation containing 
tannin. [There can be no doubt that such preparations are useless 
in amoebic dysentery. — Tr.] 

Copper sulphate in doses of 0.1-0.2 gm. (maximum dose 1.0 gm.), 
introduced in dilute solution into the stomach, after a few minutes 
causes emesis and nausea which last for only a very short time. If 
the vagi have been divided in animals so that the reflex action through 
the stomach is prevented, copper sulphate causes no vomiting. 

Reputed Toxic Action. — Under ordinary conditions the rapid ex- 
pulsion of the stomach contents keeps this salt from damaging the 
mucous membrane to any appreciable extent, but) even if it does pass 
into the intestine with the stomach contents, it is absorbed very slowly 
and in very small amounts. Consequently harmful effects due to its 
action after absorption are unknown, even when for months small 
doses have been administered daily (Toussaint, Burget, Lehmann). 
The supposed poisonous character of acid foods which have stood in 
copper vessels is almost certainly not due to their containing salts of 
copper. For these various reasons copper sulphate may be stated to 
be a relatively safe drug, which can produce a severe gastro-enteritis 
only in case exceedingly large doses, amounting to several grammes, 
be administered at one time, in which case it is also possible that sys- 
temic poisoning could result. [The prohibition of copper as a color- 
ing agent for foods is not justifiable from a hygienic standpoint. — Tr.] 

In molluscs copper and zinc also occur in considerable amounts as normal 
organically combined constituents of the protoplasm (Mendel and Bradley). 
Plants, too, absorb considerable amounts of copper from soils containing it with- 
out disturbance of their growth, and in fact under some conditions apparently 
with beneficial effects. When copper in the form of copper alkali-album inate 
or tartarate, which do not coagulate proteid, is injected subcutaneously or intra- 
venously for the purpose of causing a systemic intoxication, even small amounts 

* [In dysentery ipecac is best administered in salol-coated pills, each con- 
taining 0.3-4 gm. of the finely powdered root. — Tr.] 

f[With the above view of the method of action of ipecac in amoebic dysen- 
tery few who have had experience with this disease will agree. The translator, 
like many others, is convinced that ipecac properly employed is the most effective 
curative agent that we possess for amoebic dysentery. Recent clinical experiences 
with emetine hydrochloride administered subcutaneously speak very strongly 
for the assumption that emetine is the efficient curative agent in such cases. — Tr.] 



PERIPHERAL EMETICS 183 

exert a paralytic action on the central nervous system as well as on the striped 
muscles, and cause manifold degenerations of the tissues, particularly in those 
of the kidney, while in larger doses it kills by acute paralysis (E. Harnack). 

Therapeutically copper sulphate is employed as a rapid and cer- 
tainly acting emetic, but it is hardly possible for it to cause a persistent 
enough mild nausea for it to act as an expectorant. At the present 
time it is not possible to formulate any indications for its administra- 
tion with the idea of its acting after absorption. It is, however, of 
particular value as the antidote in acute phosphorus poisoning [as it 
acts not only as an emetic but also as a chemical antidote. — Tr.] 

Zinc sulphate has the same emetic action as copper sulphate. The 
medicinal dose is 1.0 gm. per dose and per diem. The fact that nowa- 
days it is seldom used as an emetic is difficult to understand, particu- 
larly as the danger of zinc poisoning is quite as slight as that of 
copper poisoning. Just as copper is present in preserved vegetables 
and fruits colored green with copper, considerable amounts of zinc are 
present in fruits dried in zinc trays, but harmful results due to the use 
of such dried fruits are unknown. The same is true of the effects 
of the long-continued administration of non-corrosive zinc compounds, 
even though zinc is slowly absorbed and stored up in all the organs 
of the body. 

According to Javillier, zinc, like iron and manganese, is a regular con- 
stituent of vegetable protoplasm. When present in very slight concentration, it 
stimulates the growth of yeast and also of grains. 

Zinc compounds, particularly zinc oxide, were formerly employed 
as supposedly curative agents in chorea, epilepsy, and other nervous 
diseases. From the few facts known to us of the manner in which zinc 
acts, as learned from pathological experiments, it is not possible to 
form any opinion as to the possibility of zinc's exerting any curative 
action in such diseases. 

Tartar emetic, antimony and potassium tartrate, like all other 
soluble antimonial compounds, introduced into the stomach or intes- 
tine, reflexly causes decided nausea and, as a rule, but not always, 
vomiting. 

Toxic Actions. — At the same time this salt, depending on the length 
of time that it remains in the alimentary canal, produces a more or 
1< fifl deep and extensive corrosion of the epithelium of the mucous 
membranes, and thus opens the path for its absorption into the blood 
and lymph-vessels. Moreover, even when the gastric and intestinal 
mucous membranes remain uninjured, antimony may be absorbed and 
cause a systemic poisoning, which in all essential particulars resembles 
that caused by arsenic. This consists in genera] paralysis of the capil- 
lariea (Schmicdcbcrg), weakening of the heart's action, and extensive 
exfoliative enteritis, which is due in part to an abnormal transudation 
into the villi resulting from the paralysis of their capillaries and in 



184 PHARMACOLOGY OF. THE DIGESTION 

part to the direct cytotoxic effect of the antimony, which is re-excreted 
through these mucous membranes. In addition there is paralysis of 
the central nervous system, with increasing apathy and motor paralysis. 

These actions render the soluble antimony salts extremely danger- 
ous poisons, which are all the more dangerous because occasionally 
vomiting fails to occur, so that quite large amounts of antimony 
may be absorbed. The administration of 0.2 gm. of tartar emetic in 
solution has more than once caused death in adult human beings 
(Taylor). It should consequently be the rule, in case this drug be 
used at all as an emetic, that if vomiting does not follow within an 
hour its administration should be followed by a dose of tannic acid, 
which renders this poison insoluble in the alimentary canal and thus 
interferes with its action. In the German and Austrian pharmaco- 
poeias, the maximal dose of 0.2 gm. per dose, 0.5 gm. per diem, has 
been reduced to 0.1 gm. and 0.3 gm. 

As an Expectorant. — Tartar emetic is not at all suitable for the 
purpose of producing simply persistent nausea (expectoration), but 
if any preparation of antimony is to be used for this indication it 
should be the insoluble sulphide of antimony Sb 2 S 5 , only small amounts 
of which are dissolved by the acids of the stomach. 

Externally tartar emetic, applied in concentrated solution or rubbed in as 
a salve, causes after some time burning and inflammation and the formation 
of pustules entirely similar to those of variola. Moderately severe dermatitis 
has occasionally resulted from the wearing of clothes the materials of which 
contained antimony {Lehmann u. Gobel). While formerly much used as a deriva- 
tive, the use of such salves has been correctly abandoned. 

Systemic Actions. — To-day, except in the treatment of psoriasis of 
long standing (Boeck u. Danielsen), hardly ever is use made of 
the chronic systemic actions of small doses of antimony, which are 
the same as those of arsenic, expressing themselves in similar altera- 
tions of the metabolism, the anabolism and catabolism of the tissues. 
This is probably due to the fact that they cannot be obtained with 
so little disturbance as by arsenic, for the soluble arsenical compounds 
are readily absorbed and consequently do not remain in the alimen- 
tary canal long enough to cause any irritation, while the antimony 
salts are absorbed so slowly that they are very apt to cause nausea 
and vomiting and even severe damage to the tissues* In all proba- 
bility it should be possible with suitable organic antimonial compounds 
to obtain all the therapeutic effects of arsenic, including the etiotropic 
ones (see Atoxyl, etc.). 

BIBLIOGRAPHY 

Bohm u. Unterberger: Arch. f. exp. Path. u. Pharm., 1874, vol. 2. 
Burget, Ducon et Galippe: Arch, de Phys., 1887, vol. 4. 
D'Ornellas: Bull. med. d. 1. Soc. de Ther., 1873. 

* Radziejewski (Dubois' Arch., 1871) after the administration of 0.12 gm. 
of tartar emetic recovered 0.11 gm. from the vomited material. 



EMESIS 185 

Duekworth: St. Barthol. Hosp. Rep., 1869-1871. 

Harnack, E.: Arch. f. exp. Path. u. Pharm., 1874, vol. 3. 

Javillier: Bull. Science pharinacol., 1908, vol. 15, p. 129. 

Lehmann: Arch. f. Hygien., 1S98, vol. 31, literature. 

Lehmann u. Gobel: Arch. f. Hygien., vol. 43. 

Mendel and Bradley: Am. Journ. of Phys., 1905, vol. 14. 

Polichromie: These de Paris, 1874. 

Radziejewski : Dubois' Archiv, 1871. 

Taylor: Die Gifte. Deutsch von Seydeler, 1863. 

Toiissaint: 1857, Vierteljahrschr. f. ger. Med., vol. 12. 

Wild: Lancet, 1895. 

Emesis as an undesirable side action often results from the spas- 
modic contractions of the gastric and intestinal muscles caused by 
poisonous doses of lead, barium, fly-agaric (poisonous mushrooms), 
and tobacco, as also not infrequently when pilocarpine is adminis- 
tered medicinally. The vomiting which occurs after small doses of 
morphine almost always in dogs, and not infrequently in man, is prob- 
ably due not only to a central action (see p. 34) but also to a reflex 
which is excited by the spasm of the sphincter of the pylorus produced 
by morphine (Magnus) (p. 189). 

TREATMENT OF VOMITING 

The vomiting caused by morphine may often be prevented or 
relieved by small doses of atropine (Guinard), which diminishes 
or relieves the spasm of the sphincters of the antrum of the pylorus 
and of the pylorus itself (Meltzer and Auer). The vomiting caused 
by pilocarpine is also relieved by small doses of the antagonistically 
acting atropine, which, however, to a greater or less degree inhibits 
the other actions of pilocarpine. 

Just as the algesic nerve-endings in the skin, and those in the 
mucous membranes, the peritoneum, and probably everywhere in the 
body, may as a result of inflammation become hypersusceptible to an 
<xl nine degree, and may in such cases react to stimuli which ordinarily 
are ineffective, so, too, the specific nerve-endings in the pharynx and in 
the abdominal organs, through which the vomiting reflex is excited, 
may also become hyperexcitable when these tissues become inflamed, 
so that vomiting may occur spontaneously or as the result of any irri- 
tation which may be present. Examples of vomiting thus induced are 
the vomiting in gastritis, gall-stone colic, strangulation of the intes- 
tines, etc. In such cases excessive and distressing vomiting may be 
relieved by lessening the irritation or by narcotizing the irritated 
regions by means of cocaine, orthoform, etc., or by cold, — for example, 
by swallowing pieces of ice. When vomiting is due to other causes 
loss well understood, — for example, the hyperemesis of pregnancy, sea- 
sickness, etc., — we must endeavor to relieve it by narcotizing the 
vomiting centre by large doses of morphine with y 2 m "- °f scopo- 
lamine administered subcTitaneously, or bv the rectal administration 



186 PHARMACOLOGY OF THE DIGESTION 

of chloral and by other similar procedures. Possibly the application 
of ice to the back of the neck, which is occasionally effective, acts in 
a similar fashion. 

BIBLIOGRAPHY 

Guinard: Lyon med., 1895, vol. 27, Nos. 35 and 3G. 
Magnus: Pfliiger's Arch., 1908, vol. 122. 
Meltzer u. Auer: Am. Journ. of Physiol., 190G. 

NORMAL MOVEMENTS OF THE STOMACH 

By the normal movements of the stomach solid and liquid foods are 
churned about in the fundus, in which the hydrochloric acid and much the largest 
part of the pepsin is secreted, and are permitted to pass gradually in a par- 
tially digested condition into the antrum of the pylorus, from which, after 
further preparation, they are shoved along little by little into the duodenum. 
This gradual movement of the stomach contents is controlled by three sphincters, 
the cardia, the sphincter antri pylori, and the sphincter pylori. The first two 
of these close the fundus off from the oesophagus and from the antrum, so as to 
permit it to act without interference, while the sphincter of the pylorus sees to 
it that the properly prepared and acidified chyme passes in properly measured 
portions into the duodenum, where it is further modified and passed along. 

As, like every other ferment reaction, the hydrochloric acid-pepsin diges- 
tion is very markedly retarded by dilution with water, a provision is made to 
prevent the admixture of fluids with the contents of the fundus and to allow 
them to pass along into the antrum in a sort of muscular trough, which runs 
along the small curvature above the fundus and its contents (Kaufmann, Colin- 
In i i,i i . 

When the stomach is filled, active but not very extensive peristaltic move- 
ments of the fundus occur, by means of which its contents are brought into 
contact with the gastric juice as it exudes from the mucous membrane. For 
the performance of this function the fundus constantly accommodates itself 
to its contents, dilating reflexly without any increase of tension pressure as it 
grows fuller, and contracting again as its contents pass into the antrum 
(Sick u. Tedesko), the fundus behaving here similarly to the bladder. If as 
a result of sudden overfilling of the fundus the pressure within it rises to 
about 25 cm. of water, the cardia opens so that regurgitation or vomiting may 
occur (Kelling). In the antrum of the pylorus the peristalsis is much more 
active, and is powerful enough to mix its contents thoroughly and to force it 
out through the pylorus. 

I n nervation. — The reflex coordinating mechanism for these peristaltic move- 
ments of the stomach is situated in Auerbach's plexus, which receives stimu- 
lating impulses through the vagus and inhibitory impulses from the sympathetic. 
In a similar fashion the function of the pyloric and cardial sphincters is con- 
trolled by ganglia supplied by the vagus and the sympathetic (Openchoicski) . 
Division of both the vagi and the sympathetics is not followed by any essential 
alteration of the gastric automatism or reflexes, but when the A'agi alone are 
divided the unopposed constant inhibitory effect of the sympathetic causes 
permanent disturbance of the gastric motor functions (Cannon-). 

The normal muscular movements of the stomach may also be reflexly 
stimulated or inhibited in a reflex manner by chemical action on the gastric 
mucous membranes or by a direct action on its motor nervous mechanism. 

Such reflexes are excited normally by the food and by the gastric juice, 
the hydrochloric acid of which furnishes the necessary stimulation for the 
movements of the stomach (Edelmann). Peristalsis is also excited by carbon 
dioxide, the partial pressure of which in the fasting stomach amounts to 30-50 
mm. Hg, but which during digestion may rise to 130-140 mm. Hg (Rchierbeck) . 
This effect is also produced when beverages containing carbonic acid are drunk 
or when sodium bicarbonate is administered. Those peristaltic movements of the 
antrum of the pylorus (by which the food is expelled into the duodenum) and the 
opening of the pylorus (which cooperates with them) are consequently seen to be de- 
pendent on the normal acid reaction of the stomach contents, an alkaline reaction 



GASTRIC MOTILITY 187 

of the stomach contents leaving the pylorus closed, while too high acidity may 
cause a persistent pyloric spasm. Otherwise the pyloric peristalsis is governed 
almost entirely in a reflex fashion by the chemical composition of the duodenal 
contents, alkalinity exciting the emptying mechanism while acidity or unsaponified 
fats inhibit it. This explains the so-called indigestibility of greasy or very acid 
foods such as unripe fruits, which remain for a long time in the stomach, being 
able to leave it only as rapidly as they are absorbed or neutralized in the small 
intestine or pass along into the colon. 

BIBLIOGRAPHY 

Cannon : Zentralbl. f . Physiol., 1906, vol. 20. 
Cohnbeim: Miinchn. med. Woch., 1907. 
Edelmann: Diss., 1906, Petersburg, russ. (Maly, 1906). 
Kaufmann: Ztschr. f. Heilk., 1907, vol. 28, No. 7. 
Kelling: Arch. f. klin. Chir., 1901, vol. 64, p. 393. 
Openchowski: Zentralbl. f. Physiol., 18S9. 
Schierbeck: Skand. Arch. f. Physiol., 1891, vol. 3. 
Sick u. Tedesko : Deut. Arch, f . klin. Med., 1908, vol. 92. 

IXELUEXCE EXERTED BY DRUGS OX GASTRIC MOTILITY 
In a reflex fashion the normal peristalsis of the stomach may 
hardly be affected by drugs, but it is possible that the bitters stimu- 
late it (Batelli, Heubner) . 

The more concentrated solutions of neutral salts are, the more 
do they inhibit the movements of the stomach, and it is found that 
magnesia compounds and sugar solutions inhibit it to a greater extent 
than do the sodium salts. This is the reason why only those mineral 
waters which contain very small amounts of salts are used as table 
waters, for the more concentrated ones only retard the emptying 
of the stomach and so cause discomfort. For the same reason, during 
water-cures the stronger mineral waters should always be taken when 
fasting and as long as possible before eating. The temperature of the 
water is also not without importance, for warm drinks are passed 
along through the stomach more rapidly and cold ones more slowly 
(Dapper u. v. Noorden). 

The motor function of the stomach can be influenced in a much 
more effective fashion by the direct action of "autonomic" drugs. 

EXCITATION BY " AUTONOMIC " DRUGS 

Poisoning with pilocarpine, physostigmine, and nicotine causes 

violent atypical gastric peristalsis and readily causes reflex vomiting. 

Choline, (CH,) a NOH CJI.,0, also augments tlie vagus tone and gastric 
peristalsis, but much less strongly than the above-mentioned drugs. Neurin, 
(OH I i NOB C,H„ which under some circumstances — for example, under the 
influence of bacteria {B. Hchmidt) — is formed from choline, is a powerful ex- 
citant nf the autonomic organs. As choline is a normal constituent of Hie body 
lluicls iiinl in some diseases occurs in increased amounts, either choline or the 
neurin formed from it may possibly be the cause of the increased activity of the 

movements of the stomach and intestine. It is possible also that during digestion 

it is produced in larger amounts than during fasting, and that it' consequently 
causes an augmentation of the tone of the vagus, which apparently is necessary 
during digestion. 



188 PHARMACOLOGY OF THE DIGESTION 

la this connection it may be mentioned that a number of other drugs excite 
gastric and intestinal peristalsis, particularly ergot in (Auer u. Meltzer) and 
the difiitalis glucosides, and that consequently the gastric function may be 
markedly disturbed by the medicinal use of these drugs. 

However, the indication to use such stimulating drugs for the 
purpose of reviving and augmenting gastric peristalsis does not exist 
practically, for in simple gastric atony a temporary strengthening of 
the gastric peristalsis lasting about an hour would hardly be of any 
benefit, and this is all that such drugs could accomplish. Strychnine 
is often prescribed to increase the tone of the stomach, but there is no 
experimental evidence that it does so (Langley and Magnus, Paderi). 

BIBLIOGRAPHY 

Auer and Meltzer: Am. Journ. of Physiol., 190G, vol. 17. 

Batelli: Diss., Genf., 1896. 

Dapper u. v. Noorden: Einfl. d. Mineralwasser auf d. Stoffw. in Hdb. d. Pathol, d. 

Stoffw., 1907. literature. 
Heubner: Therap. Monatsh., 1909, No. 6. 

Langley and Magnus: Journ. of Physiol., 1905-07, vols. 33 and 36. 
Paderi': La Therapie mod., 1892, No. 12. 
Schmidt, E.: Arch. d. Pharm., 1891, p. 481. 

INHIBITION OF GASTRIC MOVEMENTS 
Atropine inhibits the contractions of the gastric muscles, and thus 
may be of therapeutic value in all those conditions in which the 
indication is to moderate too violent gastric peristalsis or in any 
inflammatory and painful conditions of the stomach wall. For 
example, in gastric ulcer there is an indication for quieting the stom- 
ach as far as is possible and of relaxing reflex pyloric spasm (Schick). 
Although small doses (of 1.0-2.0 mg.) by no means paralyze the 
motor ganglia of the gastric Auerbach's plexus, they do depress or 
paralyze the vagal motor nerve-endings which are physiologically con- 
nected with it (Auer u. Meltzer), while the inhibitory sympathetic 
nerve-endings are paralyzed only by such large doses as are never 
used in practice. Consequently, the result of the administration of 
moderate doses is that the inhibitory impulses gain the upper hand 
and the stomach is quieted, an effect which is the more striking the 
more pronounced the previous stimulation of the vagus nerve-endings 
has been, — for example, after administration of pilocarpine or choline. 

In those conditions in which the activity of the stomach movements is due 
to a diminished inhibitory tonus, less effect is to be expected from atropine, 
and, as epinephrin stimulates the sympathetic nerve-endings which are here 
inhibitory organs, this drug should be the more effective gastric sedative. How- 
ever, this is at present only of theoretical importance, for when introduced into 
the stomach or administered subcutaneously epinephrin is entirely ineffective 
and even when injected intravenously acts for only a few minutes. 

Morphine produces a very peculiar effect on gastric motility. In 
dogs with duodenal fistula Hirsch observed that the emptying of the 
stomach was markedly retarded by morphine. Using Cannon's X-ray 



GASTRIC MOTILITY 189 

method, in which the food is mixed with bismuth subnitrate and thus 
may be rendered visible on the fluoroscope, Magnus investigated this 
phase of its action on dogs and cats. He found that under the in- 
fluence of a few centigrammes of morphine the food remained in the 
distended fundus, while the middle portion of the stomach, correspond- 
ing with the sphincter of the antrum, remained strongly and per- 
sistently contracted. Under these conditions the peristalsis of the 
pyloric portion remained normal and could be readily seen, but the 
pylorus itself was also tonically contracted, and when the contents of 
the stomach finally passed into the antrum this constriction of the 
pylorus retarded for hours its entrance into the duodenum (see 
Fig. 13). 

As a result, the stomach contents left the stomach not after 2-3 
hours, as occurs ordinarily, but only after 8-12-24 hours, and, as 
may be readily understood, in a condition of more advanced digestion 









Fig. 13. — Cat's stomach filled with bismuth and potato puree, a, before injection of morphine-, 
b, 22 minutes after injection of morphine; c, 1 hour after injection of morphine, spasm of the 
sphincter antri pylori; d, 3 hours after injection of morphine. 

and in a more fluid form than ordinarily. It is clear, however, that, 
as a result of remaining so long in the fundus, fermentation of the 
stomach contents may under these conditions occur to a disturbing- 
degree, just as in conditions of motor insufficiency of the stomach 
due to pathological causes, a fact which should be remembered in 
treating gastritis, ulcer, and similar conditions. This retardation of 
the emptying of the stomach by morphine may also affect the rapidity 
with which drugs are absorbed. 

In man these effects on the gastric motility result only from rather 
htriji r doses of morphine, amounting to one centigramme or more. 
Smaller doses, such as 5.0 milligrammes administered subcutaneously 
or by mouth, usually increase the peristaltic movements of the 
stomach without causing spasm of the pylorus, and are apt to accele- 
rate the rate at which the stomach is emptied (v. d. Velden). 

The same accelerating influence of small doses has been observed in dogs, 
in which ;ii tin' Bame time the secretion of the gastric juice is distinctly inhibited, 
so tliat the stomach contents reach the duodenum in a less digested and drier 
condition than normally, but some hours later free secretion of the gastric juice 
occurs spontaneously (Gohnheim). 



190 PHARMACOLOGY OF THE DIGESTION 

BIBLIOGRAPHY 

Cohnheim: u. Modrakowski: Z. f. physiol. Chem., 1911, vol. 71, p. 273. 

Hirsch: Zentralbl. f. inn. Med., 1901, vol.. 33. 

Magnus: Pfluger's Arch., 1908, vol. 122, here literature. 

Schick: Wien. klin. Woeh., 1910, No. 34. 

v. d. Velden: Verh. Kongr. inn. Med., Wiesbaden, 1910, p. 339. 

THE MOVEMENTS OF THE INTESTINE 

The movements of the intestine consist: 

First, of interrupted progressive rhythmic contractions of the 
circular and longitudinal fibres, the so-called pendulum movements, 
which have for their object the division, mixing, and moving about of 
the contents of the intestine ; 

Second, of the true peristalsis, which is excited reflexly by the 
distention and chemical stimulation caused by the intestinal contents, 
and in which tonic contraction above the stimulated portion and 
relaxation below it gradually moves the intestinal contents downward 
and finally aids in expelling the fasces (Bayliss and Starling) ; 

Third, violent sudden waves of contraction passing downward 
over large segments of the small intestine, the so-called rolling move- 
ments (Braam Houkgeest, Cannon, Meltzer and Auer), which force 
the intestinal contents forward through long stretches of the small 
intestine, and which, according to Meltzer and Auer, are exited by a 
simultaneous augmentation of the vagus tone and weakening of the 
sympathetic inhibitory impulses. 

All these intestinal movements, like those of the stomach, are con- 
trolled by the automatic action of Auerbach's plexus, and also by 
stimulating impulses through the vagus and the hypogastric and 
inhibiting impulses from the sympathetic through the splanchnic. 

PHARMACOLOGICAL ACTIONS ON THE PERIPHERAL AUTONOMIC 
ORGANS 

Consequently, all the intestinal movements, like those of the 
stomach, may be influenced by autonomic drugs, and may be excited, 
and, under certain conditions, to such an extent that tonic contraction 
results, by the action of pilocarpine, physostigmine, etc., on the vagus 
nerve-endings, while they may be suppressed by atropine in so far as 
they are due to excitation produced by vagal impulses. In veterinary 
medicine pilocarpine and physostigmine are used in colic occurring 
in horses and cattle, while physostigmine, in the form of subcutaneous 
injections of y 2 -1.0 mg. of its salicylate, has recently been employed 
in human patients for the purpose of securing rapid and complete 
emptying of the bowels. These autonomic drugs act essentially only 
on the vagus endings, — that is to say, they act independently of the 
automatic Auerbach's plexuses and of the sympathetic nervous system. 

Auerbach's system, correct^ named by Langley the " enteric sys- 
tem," acts entirely independently and maintains the automatic and 



MOTOR FUNCTION OF INTESTINE 



191 



reflex play of the intestinal movements (Magnus). Its stimulation, 
however, never causes a tonic contraction of the bowel, such as occurs 
from strong stimulation of the vagus endings, but only a strengthen- 
ing and acceleration of the contractions. Its ganglia are stimulated 
by small doses of atropine and nicotine and also by strychnine (Lang- 
ley and Magnus), and are paralyzed by larger amounts of atropine 
and nicotine, which, however, are so large that in man these effects 
are never observed, not even in poisoning by these drugs. 

PHARMACOLOGICAL ACTIONS ON" THE PERIPHERAL SYMPATHETIC 
ORGANS 

All the motor impulses from Auerbach's plexus and from the vagus 
taken together can, however, be inhibited by strong stimulation of the 




& Vagus plexus on the , 



Inhibiting nerve-endings which 
are excited by epinephrin. 



Vagus nerve-endings which are excited 
by pilocarpine, choline, etc., and para- 
lyzed by small amounts of atropine. 



sympathetic nerve or of its terminal organs. This may be produced 
by small doses of nicotine, which stimulate the sympathetic ganglia 
and also temporarily the sympathetic nerve-endings, and can be even 
more effectively produced by epinephrin, which, when injected intra- 
venously, acts on the sympathetic inhibitory mechanism in the walls 
of the intestine and causes their muscles to relax and remain quiet. 

Those movements of the intestine which are excited by anything 1 acting 
directly upon the intestinal musculature independently of any action on its ner- 
vous mechanism, are not at all inhibited by atropine and but slightly or not at 
all by epinephrin. Such probably myogenic excitation may be caused by salts 
of barium, and somewhat less energetically by poisons of the digitalis group 
{Magnus). However, such pharmacological actions are of no practical signifi- 
cance. 

These facts and relationships may be diagramatically indicated 
as in Fig. 14. 



192 PHARMACOLOGY OF THE DIGESTION 

Atropine's pharmacological actions in the intestine are particu- 
larly remarkable. These are in part of an opposing or contradictory 
nature, for through Auerbach's plexus this drug excites motor activ- 
ity while by benumbing the excitomotor nerve-endings of the vagus 
it relaxes and quiets them. If to begin with the vagal tone is not con- 
siderable, administration of atropine will produce little effect upon it, 
but in such case it will markedly augment the rhythmic and reflex 
nervous stimuli originating in Auerbach's plexus, and as a result peri- 
stalsis will be actively augmented. 

The opposite effect will be produced if at the time of its adminis- 
tration the vagal tone is exerting a strongly preponderating influence, 
as is the case in cerebral vagus stimulation or in spasm produced 
by the action of pilocarpine, neurin, etc., in lead poisoning, or in 
inllammatory irritation. In such conditions atropine, even in small 
doses, will eliminate the chief factor causing the abnormal tonic con- 
tractions, and in this fashion it will cause relaxation and quieting of 
the intestine. 

The above explains the employment of belladonna preparations — 0.02-0.05 
gm. of the extract by mouth or % -2.0 mg. of atropine sulphate subcutaneously — • 
on the one hand in a tonic constipation, either alone or combined with cathartics, 
and on the other hand in spastic constipation, in which a persistent abnormally 
increased tone of certain portions of the intestines, particularly of the internal 
sphincter (Frankl-Hochwart u. Frohlich) , exists, or in the acute inhibition of 
all intestinal movement caused by a localized spasm of the intestinal muscle 
such as occurs in ileus or intussusception. 

Morphine, the constipating action of which has long been known, 
also acts on the intestine at various points. The constipation induced 
by it is due to several factors, one important one being the persistent 
closure of the pylorus which has been already mentioned, and which 
greatly retards the passage of the chyme into the intestine, thus les- 
sening the natural stimulus for peristalsis (Magnus), while the tem- 
porary inhibition of gastric and pancreatic secretion produces a 
similar effect (Cohnheim u. Modrdkowshi) . In addition, morphine 
diminishes the excitability of the vagus endings and also of the sen- 
sory nerve-endings in the walls of the intestines (Jacob j, Pohl, Spitzer) 
and augments the spinal tone of the inhibitory splanchnic nerve (Pal 
ii. Berggriin, Spitzer). 

The above experimentally proved statements are, it is true, not 
generally accepted, but have in no way been contradicted. Recently 
they have received a certain confirmation by the observation that the 
violently increased peristalsis in the large and small intestines caused 
by decoctions of colocynth is visibly quieted by morphine, and even 
more efficiently by opium, while the accompanying inflammatory 
transudation of fluid into the intestine is markedly diminished (Padt- 
berg). On the other hand, in cats, in which inflammatory irritation 
of the small intestine was causing abnormally active peristalsis, this 
quieting effect of morphine could not be observed (Magnus). 



MOTOR FUNCTION OF INTESTINE 193 

It is not known whether or not the ileocolic sphincter is, like that 
of the pylorus, tonically contracted by morphine, but it is probable 
that this is the case. 

From the above it may be seen that under certain conditions mor- 
phine may cause the intestine to become entirely or almost entirely 
quiet. Such a quieting- of movements being- of essential value in 
treating inflammatory processes, not only in the intestine but in all 
organs, it follows that opium is one of the curative agents which could 
least be spared in acute peritonitis and enteritis. The fact that it 
has not been possible to observe with the X-ray methods this quieting 
of the intestine by morphine in no way speaks against its exerting this 
action, for the effect of the drug depends on the momentary tone and 
functional capacity of the inhibitory splanchnic centres and nerve- 
endings, and we do not as yet know how these or the automatic 
Auerbach's centres behave in an intestine which is inflamed and 
hypera?mic* As, furthermore, morphine also inhibits the secretion 
of the succus entericus, this action will also aid in causing constipation 
and in quieting peristalsis. It goes without saying that, in addition, 
the general action of morphine in relieving pain may also be of value 
in these conditions by calming the patients and softening the reflexly 
contracted abdominal muscles, etc. 

Opium is more efficient than pure morphine when the indication 
is simply to quiet the stomach and intestine, for the other alkaloids 
contained in opium also have a constipating but almost no narcotizing 
action,f so that the desired end may be attained by a smaller £ and 
less narcotic dose of opium than of pure morphine (Gottlieb u. v. d. 
Eecklwitt). 

BIBLIOGRAPHY 

Baylies and Starling: Journ. of Physiol., 1899, vol. 24, and 1902, vol. 2f>. 

Cannon: Am. Journ. of Physiol., 1902, vol. 6. 

Cohnheim u. Modrakowski : Ztschr. f. physiol. Chem., 1911, vol. 71, p. 273. 

v. l'rankl-Hochwart u. Frohlich: Pfliiger's Arch., 1900, vol. 81, p. 420. 

Gottlieb u. v. d. Eeckhout: Arch. f. exp. Path. u. Pharm., Suppl., 1908. 

Houkgeest, Braam: Pfliiger's Arch., 1872, vol. 26. 

Jacobj: Arch. f. exp. Path. u. Ther., 1891, vol. 29. 

Langley an.] Magnus: Journ. of Phys., 1905, vol. 33, and 1907, vol. 30. 

Magnus: Pfliiger's Arch., 1904, vol. 102; 1905, vol. 108; 1908, vol. 122, p. 261. 

Meltzer u. Auer: Am. Journ. of Physiol., 1907, vol. 20, here lit. 

Padtberg: Pfliiger's Arch., 1911, vol. 139, p. 318. 

I';il u. Berggriin: Strieker's Arb., 1890. 

Pohl: Arch. f. exp. Path. u. Ther., 1894, vol. 34. 

Schick: Wien. klin. Woch., 1910, No. 34. 

Bpitzer: Virchow's Arch., 1891, vol. 123. 

CATHARTICS 
Cathartics arc medicines which accelerate or bring about the 
passage of the intestinal contents along the alimentary tract and <-;msi> 

* See the action in irritation caused by colocynth, p. 102. 
t At any rate in cats. 

X Smaller, that i-. in respect t<> the amount of morphine contained. 
18 



194 PHARMACOLOGY OF THE DIGESTION 

emptying of the bowel. The act of defecation is accomplished by the 
simultaneous peristaltic contraction of the rectum and the opening of 
the internal sphincter of the anus, while at the same time colonic 
peristalsis is reflexly excited. It is not exactly known just what 
normal impulses in the rectum inaugurate the initial reflex for defeca- 
tion, but probably a certain degree of fulness and of consistency of 
its contents form the adequate stimulus, although the desire for stool 
may be present even when the rectum is empty, as in tenesmus, and, 
on the other hand, may for a long time be lacking in spite of marked 
and at times in spite of immoderate distention by solid fecal matter. 
Probably this is due to the fact that the excitability of the rectal reflex 
mechanism varies greatly under various conditions. 

Enemata, etc. — As a rule, defecation may be artificially excited 
by strong local irritation of the rectum, produced either by mechanical 
distention with a sufficiently large amount of fluid rapidly injected, 
or induced chemically by the employment of proper substances. 
Enemata of water act in the former fashion, the coldness of the 
fluid augmenting the effect ; while various irritating substances act 
in the latter fashion, for example, solutions of soap or soap cones, 
enemata. of concentrated solutions of salt, or, in an especially con- 
venient manner, a few cubic centimetres of glycerin, which, like the 
salts, stimulates the nerves in the mucous membrane as a result of 
its power of attracting water to itself. If the fecal masses in the 
colon and rectum are very hard, dry, and large, the peristaltic move- 
ments of the intestine may prove ineffectual, and in such cases it may 
be necessary first to render these fecal concretions soft and slippery. 
This is best accomplished by the gradual introduction, at body tem- 
perature and under the lowest possible pressure, through a rubber 
tube inserted as far as possible into the colon,* of 0.9 per cent, sodium 
chloride solution containing a little soda, or by injecting olive oil 
or salve-like paraffin mixtures which -are fluid at the body temperature 
(Lipoivski u. Rhode). Under these conditions the fluid may be 
retained for hours and soften the fecal concretions. 

Intestinal Colic. — As a rule, stimulation of the intestinal mucous membrane 
does not cause painful sensation, and consequently chemical or mechanical stimuli 
acting upon it never directly cause pain. Painful stimuli can, however, originate 
in the peritoneum when it is markedly stretched or chemically irritated by 
inflammatory products. Consequently, violent peristalsis of the colon and rectum, 
when they are filled with solid material, may stretch their peritoneal covering 
and in this fashion cause pain or colic. In the small intestine, whose contents 
are always fluid or partially fluid, even active muscular contractions do not 
readily cause enough distention to produce pain, but only enough to cause a 
feeling of and the noise resulting from the interrupted and irregular moving 
about of the intestinal gases. 

* [It has been definitely shown that it is impossible, under ordinary con- 
ditions, to pass either soft or stiff tubes into the colon. — Tb.] 



CATHARTICS 195 

MANNER IN WHICH CATHARTICS ACT 

Cathartic drugs produce their effects either by directly exciting 
and accelerating the intestinal peristalsis or by indirectly doing so, 
either by lessening the normal absorption or by increasing the secre- 
tion of the intestinal glands and in this way keeping the contents of 
the intestine fluid and voluminous. 

From the character of the stools it is not possible to distinguish 
sharply between these factors, for on the one hand abnormally active 
peristalsis does not allow the intestine to concentrate its contents by 
absorption of the fluid, and on the other the accumulation of abnor- 
mally large amounts of fluid in the intestine reflexly excites active 
peristalsis. 

The quantities of fluid which under the influence of the ingested 
food are poured out into the intestine in the course of the day and 
which are generally almost completely reabsorbed may amount to as 
much as several litres. 

Bidder and Schmidt have estimated them as amounting in the adult man 
to 9 litres, composed of saliva 1.5 L., bile 1.5 L., gastric juice 6 L., pancreatic 
juice 0.2 L., and succus intericus 0.2 L.; but here in all probability the gastric 
juice is estimated at too high a figure. According to newer observations in man, 
there are excreted in 24 hours: of saliva 700-1000 c.c. or more (Tuczek, 
Sommerfeld, Umber), of bile 600-900 c.c. (Ranlce, Wittich, Hoppe-Seyler) , pan- 
creatic juice 600-800 c.c. (Pfaff), gastric juice 1000-2000 c.c. {Glassner) , in all 
3-4% litres. 

From these figures it is evident that even comparatively slight 
interference with the reabsorption may result in a sufficient quantity 
of fluid material reaching the rectum to cause a soft or diarrhoea! 
stool. "When the absorption is entirely inhibited, as in cholera, con- 
tinual diarrhceal movements occur, interrupted by short periods of 
rest, and, as a result, the body loses an enormous amount of fluid and 
the blood becomes markedly concentrated {Schmidt). Under these 
conditions the fluid material evacuated corresponds exactly in its 
chemical constitution to normal succus entericus (p. 171). 

Essential Properties of Cathartics. — In order for a substance 
to be suitable for use as a cathartic, it should not act appreciably 
upon Hie gastric mucous membrane, but should become active only 
when it reaches the intestine, where, under the influence of its new 
environment, it is transformed into a substance which can excite peri- 
stalsis or secretory activity. According as this transformation occurs 
in the small intestine or only after the drug reaches the large gut, it 
will develop its cathartic action in the small intestine or in the large 
Intestine. In the small intestine the alkaline succus entericus, bile, and 
pancreatic secretion, with its fat-splitting ferment, are responsible 
tor such transformations, while in the colon they result from chemical 
reactions, more particularly from reductions due to the activity of 
putrefactive bacteria. 



196 PHARMACOLOGY OF THE DIGESTION 

Under normal conditions putrefaction does not occur in the small gut, but 
only below the ileocecal valve, as is evidenced by the presence of H 2 S in the large 
and its absence in the small intestine. 

As all cathartic actions are due to reactions taking place on the 
surface of the intestinal mucous membrane, the efficiency of cathartic 
drugs will be, at least in part, dependent on the extent to which 
they are able to act throughout the intestine. From this it may be 
concluded that cathartics must be absorbed only with difficulty or not 
at all, and that those acting in the small intestine must pass along 
through at least the largest portion of it while the others must be 
able to reach the colon. 

From these points of view the cathartics may in general terms be 
arranged in the following groups : 

1. Groups interfering with the absorption throughout the 
whole intestine. — In this group are included those substances which 
act osmotically, such as the poorly absorbable salts and sugars and 
also calomel. According to circumstances and the concentrations 
administered, they produce their effect in from one to twenty hours 
and with more or less rumbling of the bowels but without much colic. 

2. Drugs whose chief action is on the motor functions of the 
small intestine. — These include certain oils, colocynthin, and a num- 
ber of resinous acids, and act in from 2 to 4 hours with more or less 
rumbling of the bowel but without colic. 

3. Drugs which owe their effects essentially to their action 

ON THE MOVEMENTS OF THE LARGE INTESTINE. — In this group are 

sulphur, the anthracene derivatives, and phenolphthalein. They act 
in about 10-15 hours without causing rumbling of the bowels but often 
causing colicky pains. 

BIBLIOGRAPHY 

Glassner: Ztschr. f. phvsiol. Chein., 1904, vol. 40. 

Lipowski u. Rhode: Med. Klinik, 1909, No. 48. 

Pawlow: Die Arbeit d. Verdauungsdriisen, Wiesbaden, 1898, p. 106. 

Pfaff : 187.7, Journ. of the Boston Soc. of Med., vol. 2, No. 2. 

Ranke: 1871, cited from Hoppe-Seylers Handb., p. 286. 

Schmidt, C: Die epid. Cholera, Leipzig u. Mittau, 1850, p. 72. 

Sommerfeld: Dubois' Arch., Suppl., 1905. 

Tuczek: Ztschr. f. Biol., 1876, vol. 12. 

Umber: Berl. klin. Woch., 1905, No. 42. 

Wittich: 1872, cited from Hoppe-Seyler's Handb., p. 286. 

1. CATHARTICS INTERFERING WITH ABSORPTION 
GROUP OF SALINE CATHARTICS 

As has already been mentioned, solutions of crystalloids diffusing 
poorly are in general poorly absorbed {Hober, Koranyi, Richter), and, 
inasmuch as, owing to their power of attracting water, they are able 
to retain their water of solution and even at times to increase it, 
they prevent or retard the absorption of the fluid with which they are 
administered or that resulting from secretion in the small intestine. 



SALINE CATHARTICS 



197 



Consequently, they cause the accumulation in the intestine of abnor- 
mally large amounts of fluid, which pass into the colon and rectum 
and produce watery fecal discharges. This action is aided and aug- 
mented by the increased intestinal secretion which results from the 
reflex stimulation of the intestinal glands by the concentrated salt 
solution. In this fashion the sulphates, Na„S0 4 , or Glauber's salts, 
and MgS0 4 , or Epsom salts, act as particularly effective cathartics. 

This conception of the fashion in which the saline cathartics act, which is 
based upon the investigations of Buchheim and his collaborators, and particu- 
larly on those of Matthew Hay, finds its proofs in many facts, but particularly 
in the fact that the fluid bowel movements resulting from the administration 
of saline cathartics possess the characteristic properties of normal intestinal 
secretion in both their fermentative properties and their chemical composition, 
which differs quite as much from that of an inflammatory transudate or exudate 
as from that of a fluid diluted simply as a result of osmotic diffusion from the 
tissues. In every particular they correspond very closely to normal succus 
entericus obtained from intestinal fistulse, as is shown by the following table: 





E 

3 

a 

a 

a 

3 

w 


3 ° 


° o 

.2 a> 

"" a 
O 


■a 

3 
M 

3 

s 


Normal succus 
entericus 


"3 

q 

s 


Cholera stool 
(C. Schmidt) 




Moreau 


Smith 


I 


II 


Solids 

Organic 

Inorganic 


9.2 
7.6 
1.6 


8.1 
7.2 
0.9 


3.0 

2.2 
0.8 


3.4 
2.6 
0.8 


1.3 
0.4 
0.9 


1.1 

0.5 
0.6 


1.6 

0.8 
0.8 


1.2 
0.3 
0.9 


1.5 
0.7 
0.8 





Ury has recently investigated in human subjects the action of Apenta water, 
which contains about 15.5 gm. Na.SC^ and 2.0 gm. NaCl per litre, and of solutions 
of magnesium sulphate, in which he determined the composition of the evacuated 
faeces. His findings have led him to conclude that large amounts of water are 
excreted in the intestine by a sort of capillary transudation, for he found these 
stools to contain very small amounts of ferments, and he therefore concluded that 
the secretions of the intestinal glands made up but a very small portion of the 
fluid evacuated. However, it lias not yet been determined whether or not these 
ferments are not in large part weakened or destroyed during their passage through 
the lar^e intestine (Grober), and, moreover, the sodium and chlorine contents of 
the fluids evacuated, even in Ury's experiments, correspond quite closely to that 
of tin- normal intestinal secretion. 

Various other authors, and comparatively recently MacCallum, have 
assumed that the salines after absorption into the blood stimulate the motor 
and secretory mechanisms of the intestinal wall and in this fashion cause 
diarrhoea. However, in contradiction to this view, it has recently once more 
been definitely shown that intravenous or subcutaneous injections of saline cathar- 
tics do not cause diarrhoea, but that when concentrated solutions are used they 
actually cause persisted constipation, for by causing an increased diuresis 
they dehydrate the blood and tissues quite markedly [Framld, A u<r). However, 
if very large amounts of dilute salt solutions be administered subcutaneously, 
bo large a portion of this may be excreted info the intestine that it excites 
diarrhoea, just as it, does when administered internally. Further, if a concen- 
trated Ball solution be injected under the skin of the abdomen, it, like other 

Irritating substances, may cause a more or less violent local irritation, which 

may reflexly cause hyperamia and stimulation <>f the intestines innervated from 
the same segment of the spinal cord, and in this fashion cause a diarrhoea 



198 PHARMACOLOGY OF THE DIGESTION 

(Hay). From other portions of the skin, however, this reflex cannot be 
obtained. 

MacCallum's assumption was based on the observation that intravenous 
injections of very small amounts of Glauber's or Epsom salts, or the painting 
of an exposed loop of the intestine with such solutions, excited a muscular con- 
traction of the gut and a secretion by the mucous membrane. While it is 
true that this effect may be regularly obtained by the local application of such 
solutions, intravenous injections are only occasionally followed by such effect, 
and, even when it does occur, the motor stimulation lasts only a few seconds, 
or at the most a few minutes, and exerts no appreciable influence on the trans- 
portation downward of the intestinal contents or their evacuation (Frankl). 
Padtberg has also recently confirmed the correctness of Buchheim's views. 

In another indirect connection, however, MacGallum's belief in the specific 
chemical activity of the saline cathartics finds a support and basis. As already 
mentioned (see foot-note, p. 175), Wallace and Cushny have looked upon the 
calcium-precipitating power of the salines as one of the causal factors in their 
cathartic action, and it is a fact that the intestinal wall is deprived * of its 
calcium by those anions which precipitate calcium, among which is the anion 
which is formed from castor oil. This removal of calcium probably augments 
quite generally the effect of motor and secretory stimuli (/. Loeb, Chiari u. 
Frohlich). 

The concentration of the saline solutions exerts an important 
influence on their behavior and their effects in the intestine, for the 
following reasons. High concentrations (for Na 2 S0 4 10-25 per cent.) 
combine with and hold fast large amounts of the gradually secreted 
gastric juice, and continue to do this until the salt concentration has 
sunk to about 3 per cent. When this dilution has been attained, 
the solution has lost its power of combining with the water or, what in 
this case means almost the same thing, has lost the power of preventing 
absorption, and in fact a portion of such a diluted solution is absorbed 
and enters the blood, although by far the larger portion leaves the 
intestine in the watery stools. As the dilution of the saline solution — 
that is to say, the augmentation of the amount of fluid in the intes- 
tine — results practically only from the gradual secretion of the 
digestive juices, it may take many hours before the quantity becomes 
large enough to produce a diarrhceal evacuation. For example, after 
the administration of the dry salt to a dog, defecation occurs only after 
about 25 hours, and, after the administration of a 20 per cent, solution 
to man, only after 16 hours. Moreover, catharsis is produced by salts 
thus administered only if the intestine is able to furnish a sufficiently 
large amount of secretions, and this is dependent on the amount of 
water present in the blood and in the tissues. If the dog has received 
no fluid and only dry food for one or two days', the secretions of the 
alimentary tract are so scanty that a concentrated solution of Glauber 's 
salt may be administered without producing any catharsis. 

If, on the other hand, a diluted (5 per cent, or less) solution be 
administered, it does not retain the fluid secreted by the digestive 

* The calcium is in part actually removed and in part precipitated in insolu- 
ble form in the tissues forming the intestinal wall. Calomel also produces 
a similar diminution of the calcium content of the intestinal walls. 



SALINE CATHARTICS 



199 



organs, and consequently does not increase in amount, but in fact is 
somewhat diminished, because a portion of the dilute solution under- 
goes absorption. If the amount administered was by itself large 
enough, the unabsorbed portion passes rapidly into the colon and 
causes a diarrhceal stool, which may consequently occur very soon, 
in 1-2 hours, and which is quite uninfluenced by the water content 
of the blood and tissues. 



Red cells in milli 
per cu. mm. 





Ma 


in 6% 


Na,2SOi 
solution 














— , 


___.- 


-" 


■- 






1 















Red cells in millions 
per cu. mm. 

7 







- — ^^Afc 


n^=21.0 
in 25% 


NaiSOf 
solution 





























=f- 



O f 

Red cells in millions 
per cu. mm. 




Tt is thus seen that the effect of concentrated and dilute solutions 
is quite different. After administration of a laxative dose, for example 
20 gm. Na._,S0 4 , in concentrated solution, a diarrhoaal evacuation fol- 
lows in 10-20 hours and water is removed from the body, but after 
administration of a small dose in dilute solution, — e.g., 5 per cent., 
that is to say in a large amount of water, — diarrhoea follows in 1-2 
horns, and the water content of the body is not affected. These effects 
may be readily demonstrated by determining the red-coll content of 
the blood before and after the administration of the salts (see Fig. 15). 



200 PHARMACOLOGY OF THE DIGESTION 

In both cases there may be noted a temporary slight increase in the con- 
centration of the blood, which occurs very late. This is explained by the fact 
that a certain amount of the salt is absorbed and circulates around in the blood 
or is stored up in the tissues, which later, when excreted through the kidneys, 
carries with its solvent water which is thus lost by the blood. 

Prom these facts one may draw the conclusion, that, in those cases 
in which saline cathartics are to be given for a considerable period in 
order to exert curative action on the intestinal mucous membrane, 
they should be administered in dilute solutions, such as the natural 
cathartic mineral waters, and that, when they are employed to produce 
dehydration, as in dropsy, they should be given only in concentrated 
solution. Magnesium sulphate (Hay), which is soluble in an equal 
weight of water, and calcined magnesia in substance are the best drugs 
to meet this indication. 

Hay's investigations also brought to light another important fact, — namely, 
that, along witli its purgative action, magnesium sulphate causes the body to 
lose a certain amount of its alkali. This is due to the fact that, as this salt 
is in part decomposed by the carbonic acid in the intestine, considerable amounts 
of sulphuric acid are absorbed, which are later excreted in the urine, combined 
with soda and ammonia which is derived from the body. Quantitative deter- 
mination of the sulphuric acid and the magnesium excreted in the urine under 
such conditions shows that the sulphuric acid excreted in the urine is sufficient 
to neutralize about ten times the amount of magnesium excreted. It is 
thus clear that with the continued administration of this salt the body will lose 
more or less alkali. This it is able to support for a time by utilizing ammonia 
for the neutralization of the excess of sulphuric acid, but it is not impossible 
that when Epsom salts are persistently taken the organism may suffer some 
damage as a result of such constant loss of alkali, and in practice it is the 
custom, when using saline cathartics for long periods of time, almost always to 
employ them in mixtures containing alkaline carbonates, such as are present in 
the natural spring waters of Carlsbad, Marienbad, etc. 

Effects on Utilization of Food. — Inasmuch as the small intestine 
usually contains, in addition to the digestive juices, more or less food, 
an accelerated emptying of the bowel and an interference with the 
absorption must exert an unfavorable effect upon the utilization of 
the food ingested. According to the analyses available, it is especially 
the utilization of fats which suffers, this being due not only to the 
cathartic action of the magnesium salts but also to the fact that the 
fatty acids and magnesia form insoluble and consequently unabsorb- 
able soaps. While this interference with the utilization of food is not 
very great, it is an accessory factor in the reduction of weight obtained 
by the use of various salines. 

Effect on. Intestinal Flora. — Finally, among the effects of the 
thorough evacuation and flushing of the intestine by cathartics, men- 
tion should be made of their power of removing from it bacteria and 
their decomposition products, for it is quite possible that numerous 
symptoms of disease are due to the absorption of toxic substances from 
the intestine, which give rise to the so-called auto-intoxication. As all 
attempts to accomplish disinfection, not to speak of sterilization, 



SALINE CATHARTICS 201 

of the intestine by the administration of disinfectants have proved 
unavailing (Stern), the most efficient means of removing pathogenic 
micro-organisms is repeated catharsis. Calomel appears to be the 
cathartic best adapted for this indication, as its cathartic action starts 
in the small intestine and extends throughout the whole length of the 
bowel, and at the same time it possesses some bactericidal powers.* 

Effects on the Liver. — It is possible that such cleansing of the intes- 
tine plays an important role in the treatment of diseases of the liver 
and of chronic intestinal catarrhs by Carlsbad or other saline waters. 
It appears not improbable that under such conditions the increased 
blood-flow through the vessels of the intestine and of the liver, as also 
the local salt action of the sodium sulphate and the soda, which are 
absorbed into the blood and lymph, may also play an important part 
in producing curative effects. The favorable effect of the saline 
cathartics in diabetes mellitus is much more difficult, in fact practically 
impossible, to explain. 

This increased blood flow through the whole portal system resulting from 
the action of the cathartics necessarily causes a correspondingly diminished 
blood flow in other organs, such as the lungs, heart, etc. This has been spoken 
of as determination to the intestine, and is often employed as a curative or 
symptomatically favorable action in hyperemia of the brain or of the thoracic 
organs. 

The chief drugs of this group used in practice are as follows: 
the sulphates of the alkalies, particularly Glauber's salt or sodium 
sulphate, Xa 2 S0 4 -f 10H 2 O, or -f 1H 2 0, containing according to the 
amount of its water of crystallization 44 or 88 per cent, sodium 
sulphate, and Epsom salt, or magnesium sulphate, MgS0 4 -4- 7H 2 0, 
containing about 50 per cent, magnesium sulphate. These two salts, 
in doses of 15-30 gm. taken at one time or at short intervals, are 
efficient laxatives. 

All the sulphates if they remain long in the large intestine undergo 
a reduction, with production of hydrogen sulphide, an effect which 
occasionally leads to disagreeable borborygmus and flatulence. 

As Antidotes. — As sulphuric acid forms insoluble salts with barium and 
lead, the soluble sulphates may serve as chemical antidotes in lead or barium 
poisoning. .Many toxic substances, particularly the phenols, are conjugated in the 
organism with sulphuric acid from non-toxic compounds, and consequently it 
has been believed that in carbolic acid poisoning it was possible to facilitate or 
augment the distoxication of the absorbed carbolic acid by administering the 
sulphates. However, neither clinical experience nor laboratory experiments 
furnish evidence that such is the case (Tauber). 

Sodium sulphate is the most important ingredient of the waters of 
Marienbad, Carlsbad, and Tarasp, while magnesium sulphate is the 
mosl important ingredient of numerous so-called bitter waters, among 

[More recent careful investigation oi the disinfectant action of calomel in 
the intestine would indicate that it possesses none, or at Least nunc of practical 
value. See Harris, Jour, of A. M. A., 1912. — Tit.] 



202 PHARMACOLOGY OF THE DIGESTION 

which may be mentioned those of Friedrichshall, Mergentheim, Apenta, 
Hnnyadi Janos, etc. Artificial Carlsbad salts are a mixture of salts 
corresponding approximately to the residue obtained by evaporating 
Carlsbad water and contain about 44 per cent. Na 2 S0 4 -+- 1H 2 ; 6.0 
gm. of these artificial salts in one litre of water roughly represent the 
natural Carlsbad water. Magnesium sulphate is partially decomposed 
in the intestine by the carbonates of the intestinal secretions, and 
bicarbonate of magnesium is formed, which possesses the same power 
of attracting water and of causing catharsis as does the original salt. 
When this occurs, the sulphuric acid is in large part eliminated in the 
urine, temporarily increasing its acidity {Hay) (see p. 200). 

Calcined magnesia or magnesia usta, although almost entirely 
insoluble, is transformed in the intestine into the bicarbonate and 
thus acts as a cathartic. On account of its freedom from taste or 
other harmful actions, this drug may be readily administered to sus- 
ceptible patients or to small children, and may also be used with advan- 
tage to neutralize acids in the stomach and the intestine, or in poison- 
ing by metallic salts, to precipitate the metallic oxides out of their 
solutions or more or less absorbable compounds, and in tins fashion 
to render them harmless, at least for a time. 

As Antidote for Arsenic. — With arsenous acid magnesia forms a very in- 
soluble salt, and consequently it is commonly used, usually in combination with 
iron hydroxide, as an antidote in arsenical poisoning. However, experiments on 
animals poisoned with lethal doses of arsenic have indicated the uselessness of 
this treatment (de Bucher). 

Toxic Action of Magnesium. — If absorbed into the circulation, magnesium 
salts are very poisonous, even a few decigrammes administered intravenously 
to large animals being sufficient to paralyze the respiratory centre. When fol- 
lowing subcutaneous injection the toxic action develops gradually, the respira- 
tory paralysis is preceded by a complete narcosis of the central nervous system, 
which after 0.8-0.9 gm. MgCL per kilogramme of body weight lasts some hours, 
and then gradually disappears as the salt is excreted. Intravenous injection of 
calcium salts overcomes this narcosis almost instantaneously (Meltzer u. Auer) . 
Lower animals also are narcotized and paralyzed without primary stimulation 
by salts of magnesia, a fact which is well known to zoologists and utilized by 
them for the fixation of animal organisms in natural free positions (Lee and 
1'. Mayer) . 

[Boos has called attention to the very real danger of serious or 
fatal poisoning from the absorption of magnesium sulphate which has 
been given to induce catharsis and which has failed to act. The trans- 
lator is convinced that he has seen evidence of such toxic actions, 
particularly in cases of postoperative ileus. As sodium sulphate is 
equally efficient and quite harmless, it should be given the preference 
in any cases in which there is possibility of intestinal obstruction or 
paresis. — Tr.] 

Among other saline cathartics are sodium phosphate, 
Na o HP0 4 -f- 12H 2 0, containing 40 per cent, of the salt, used in dosage 
of 20-40 gm. ; the rather insoluble potassium bitartrate, KHC 4 H 4 6 , 
used in dosage of 5.0-10.0 gm., the readily soluble Seignette salt, 



CALOMEL 203 

potassium and sodium tartrate, KNaC 4 H 4 6 , + 4H 2 0, dose 15.0- 
30.0 gm., and also the citrates of tae alkalies. Tamarind, containing 
large amounts of organic acids, and mannite also produce their laxa- 
tive action in a similar fashion. 

BIBLIOGRAPHY 

Auer: Am. Journ. of Physiol., 1906, vol. 17. 

Auer: Journ. of Biol. Chem., 1908, vol. 4. 

Boos: J. of A. M. A., 1910. 

de Bucher: Arch, intern, de Pharrnacodyn., 1902, vol. 10, p. 414. 

Chiari: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 434. 

Chiari u. Frohlich: Arch. f. exp. Path. u. Pharm., 1911, vol. 64, p. 214. 

Frankl: Arch. f. exp. Path. u. Pharm., 1907, vol. 57. 

Grober: Deut. Arch. f. klin. Med., vol. 83, Nos. 3 and 4. 

Hay: The Physiol. Action of Saline Cathartics, Edinburgh, 1884, p. 160. 

Hay: The Lancet, 21st April, 1883. 

Hav: Journ. of Anat. and Physiol., 1884, vols. 16 and 17, literature. 

Hober: Pfliiger's Arch., 1898, vol. 70, p. 624, and 1899, vol. 74, p. 246. 

Koranyi-Richter: Hdb. d. physik. Chem. u. Med., 1907, p. 294 ff., Physikal. Chemie 

in der Physiol, d. Resorption. 
Lee u. P. Mayer: Mikroskop. Technik. f. Zoologen, 1901. 
Loeb, J.: Am. Journ. of Phvs., 1901, vol. 5, p. 362. 
Loeb, J.: Pfliiger's Arch., 1902, vol. 91, p. 248. 
MacCallum: Am. Journ. of Phvsiol., 1903, vol. 10. 
MacCallum: Univ. of Calif. Pu'bl., 1903, vol. 1; 1906, vol. 3. 
Meltzer u. Auer: Amer. Journ. of Physiol., 1908, vol. 21, p. 400. 
Padtberg: Pfliiger's Arch., 1909, vol. 129, p. 476. 
Stern: Ztschr. f. Hygiene, 1892, vol. 12. 
Tauber: Arch. f. exp. Path. u. Pharm., 1895, vol. 36, p. 197. 
Ury: Arch. Verd., 1909, vol. 15, No. 2. 

CALOMEL 

Calomel, the mild chloride of mercury, mercurous chloride 

(tt ^i )> should a l so De considered here. 
xi g — CI/ 

It occurs in the form of a tasteless white powder, consisting of microscopic 
crystals which are insoluble in water. By the rapid cooling of its vapor, it may 
be obtained as a very fine, almost entirely amorphous powder. The name calomel 
was given on account of the beautiful black color produced by treating calomel 

with ammonia, according to the formula ll g ^. + 2NH 3 = Hg ( NH.C1 ) 2 + Hg. 

HgCl " to 

By contact with the tissue fluids, calomel is transformed into 
soluble mercuric compounds, probably albuminates, which, without 
causing an acute local toxic action, are absorbed, and produce a mer- 
curial action which develops very gradually. In the mucous mem- 
brane of the mouth and intestine, this action causes a stimulation 
"I' glandular secretions and inhibition of absorption, so that under 
proper conditions it causes salivation and the accumulation of large 
amounts of fluid in the intestine, with the evacuation of watery 
stools. 

Mercurial salivation may bo suppressed by atroi>ine, as may also the 
diarrlma caused by it. The actions on the sal i vary ^ lands appear to be due to 
a Specific pilocarpine-like stimulation of their secretory nerves. 



204 PHARMACOLOGY OF THE DIGESTION 

Calomel stools often have a grayish-green color, which is ordinarily attrib- 
uted to biliverdin, which is supposed to escape the usual reduction to biliprasin 
on account of the disinfecting influence of calomel. However, Doyon and Eufort 
found that calomel produced the same green-colored stools even when the bile- 
duct is divided and the bile is permitted to escape through a fistula. Conse- 
quently, this green color is due to the presence of the sulphide of mercury. 

Effect on the Biliary Secretion. — The bile becomes more con- 
centrated, and is consequently secreted more slowly, as a result of the 
dehydration which results from catharsis with calomel (Doyon and 
Bufort)* 

Inasmuch as the first action of calomel is limited to its specific 
effect on secretion and absorption, and as it causes no irritation or 
inflammation, but, on the contrary, by its disinfecting action combats to 
a certain extent the harmful bacteria flora [ ? see p. 201. — Tr.] , calomel 
may be used without fear in moderate doses (0.05-0.3 gm.) in adults, 
even in the presence of diseased or delicate intestines, and also in 
small children (0.01 gm. for infants) and in pregnant women. As a 
rule, painless catharsis results from its administration. 

In order that calomel may act without doing harm, however, it 
must be rapidly and completely eliminated by the bowel. In the 
presence of a constipation due to intestinal paresis from peritonitis 
or to obstruction of the bowel, calomel is a dangerous drug, for under 
these conditions it will, little by little, go completely into solution and 
be absorbed, and cause the same symptoms of poisoning as does cor- 
rosive sublimate. Further, the administration of calomel to patients 
taking iodides should be avoided, for, when these two substances meet 
each other in the tissues, the caustic mercuric iodide is formed. 

Diuretic Effects. — The augmentation of diuresis occurring 24-36 
hours after the administration of calomel is probably dependent on the 
fact that calomel causes the accumulation of large quantities of fluid 
in the intestine, and the fact that, if this fluid is not rapidly enough 
evacuated from the large intestine, a large portion of it will be reab- 
sorbed from the colon and will cause hydremia and resulting diuresis 
(unpublished experiments). This diuresis occurs the more rapidly 
and to a greater extent the more rapidly the blood is able to replace 
from the tissues the water lost as the result of the secretion into the 
small intestine ( and this is especially the case in the presence of a gen- 
eral anasarca) , for then the fluid absorbed from the colon is added to 
the blood and causes a marked hydremia. Moreover, this general effect 
is the greater, the more slowly the colon is emptied by defecation. 
Clinical experience has taught us that calomel causes a marked diu- 
resis where these various essential conditions are present, — i.e., in cases 
with general anasarca and functionally capable kidneys, and espe- 
cially when the calomel has been given together with opium, which 
either retards the evacuation of the bowels or entirely prevents it. 

0>i the kidney itself, it appears that calomel, to the extent to which 

*Arch. de Physiol, norm, et path., 1897, vol. 9, p. 5G2. 



CATHARTICS ACTING ON SMALL INTESTINE 205 

it is absorbed in soluble modifications, does not act differently than 
bichloride of mercury and many other metallic salts, in very small 
amounts causing hyperemia and irritation and in large amounts pro- 
ducing serious damage. In the presence of nephritis it should, there- 
fore, not be given (see chapter on Diuresis, p. 356). [Many will 
disagree with this sweeping statement. — Tr.] All the other slowly 
developing actions of calomel administered internally or subcutane- 
ously and intramuscularly are the same as those of other mercurial 
compounds. For further details the reader is referred to the chapter 
on etiotropic drugs. 

II. CATHARTICS ACTING CHIEFLY ON" THE SMALL INTESTINE 
Neutral fats are passed through the stomach without undergoing 
appreciable decomposition, but are saponified in the small intestine. 
The soaps formed from the animal and most of the vegetable fats act 
as very mild irritants to the intestinal mucous membrane, accelerating 
peristalsis only when administered in considerable amounts. In this 
fashion 20-30 gm. butter taken on a fasting stomach may produce 
a mild laxative effect. However, the soap formed from castor oil 
in the intestine acts as a specific excitant of the peristalsis of the small 
intestine. 

Oleum ricini, or castor oil, is obtained by crushing the castor-oil 
bean, and by repeated filtration is freed from various impurities, — 
among others, from the poisonous proteid ricin. It has a flat, repul- 
sive taste, and in many individuals causes nausea, probably because 
it is decomposed, although only to a small extent, in the stomach. 
Its irritant action in the small intestine is not intense, and never 
enough to cause inflammatory irritation, chiefly because these ricinus 
.soaps are absorbed in the small intestine, so that their action is not 
persistent. In spite of this, however, a sufficiently powerful effect on 
the peristalsis is usually produced, for it acts on a very large portion 
of the intestine, as it passes along the gut very gradually and is only 
gradually saponified (77. Meyer). Doses of 15.0-30.0 gm. are followed 
after 6-10 hours by one or two soft stools without colic. Castor oil 
hardly ever reaches the large intestine, and consequently produces no 
effect upon it (Magnus). It may, therefore, without fear be pre- 
scribed for pregnant women. 

Croton oil, oleum crotonis, obtained from the seeds of Croton 
Helium, contains crotonoleic acid, partly in a free state, and other 
link noun substances. Consequently, wherever applied, this drug 
causes violent irritation and inflammation. In doses of 5.0-20.0 mg. 
(maximal dose, 0.05 gm. per dose) it acts ;is a drastic purgative. 
When purified by alcohol, croton oil is neutral in reaction, tasteless, 
and unirritiiting, but, owin^ 1o its sjqxminVnlion in the inlesl inc, 
even this in doses of 0.05 gm. causes violent diarrhoea (Buchheim u. 
Krich), 



206 PHARMACOLOGY OF THE DIGESTION 

Certain resinous acids appear to act similarly to ricinoleic acid. 
Among these are the resins present in the tuberous root of Ipomcea 
jalapa (Jalap) and in the root of Convolvulus scammonia (Scam- 
mony) and many others. These are all acid anhydrides of a glu- 
cosidal nature, which are insoluble in water, but which after reaching 
the intestine are transformed by the alkaline secretions, particularly 
by the bile, into soluble and active substances. They then excite 
violent peristalsis of the small intestine and perhaps also increase 
secretion, and consequently the intestinal contents are rapidly forced 
along into the colon. As, however, these resins are absorbed or de- 
stroyed only after they reach the large intestine, they cause increased 
peristalsis here also, with colic and a resulting hyperaemia and reflex 
stimulation of the other pelvic organs. Consequently, they are by no 
means so harmless as castor oil. 

In this class belongs the fruit of Citrullus colocynthis, the 
active principle of which is the exceedingly bitter glucoside colocyn- 
thin, which is soluble in water, and which in small doses, 1.0-5.0 ( !) 
eg. of the extract per dose, causes increased secretion or outpouring 
of fluid into the small intestine and probably also in the large intes- 
tine, and accelerates the peristalsis, while in large doses it causes 
vomiting and violent inflammation of the mucous membrane of the 
stomach and intestine (see p. 192). 

Similar to this is gamboge, a gum resin obtained from Garcinia 
hanburii, which, in addition to gum, contains as its active principle 
an acid which in small doses causes a watery, painless diarrhoea, and in 
large doses colic and gastro-enteritis, and at times abortion. 

Finally, mention should be made of podophyllin, a resin obtained 
from Podophyllum peltatum, the active principle of which is a crystal- 
line podophyllotoxin, which is soluble with difficulty in water. It is 
used in chronic constipation in doses of 1.0-5.0 eg., and in larger doses 
(0.1 gm. maximal single dose) as a drastic cathartic, which, when 
given in too large doses, causes violent gastro-enteritis. Podophyllo- 
toxin and colocynthin, even when given subcutaneously, cause diar- 
rhoea and at times gastro-enteritis, and at the same time they cause 
inflammation of the kidneys and abscess at the site of injection. They 
are therefore unsuitable for subcutaneous administration. 



/min, a cathartic resin contained in Euonymus atropurpureus, is 
obtained as a precipitate on the addition of water to an alcoholic extract of the 
crude drug. After precipitation of euonymin from this solution, it still contains 
a glucoside which acts not as a cathartic, but which exerts a digitalis action on 
the heart (Romm). 

BIBLIOGRAPHY 
Buchheim u. Krich: Virchow's Arch., 1858, vol. 12. 
-Johannes Miiller: Diss., Dorpat, 1885, here literature. 
Magnus, R.: Pfliiger's Arch., 1908, vol. 122, p. 261; literature here. 
Mever, H.: Arch. f. exp. Path. u. Pharm., 1891, vol. 28, p. 145; 1897, vol. 38, 

' p. 336. 
Padtberg: Pfliiger's Arch., 1910, vol. 134, p. 627. 
Romm: Diss., Dorpat, 1884. 



CATHARTICS ACTING ON LARGE INTESTINE 207 

III. CATHARTICS ACTING CHIEFLY ON THE LARGE INTESTINE 
This group is composed of a number of drugs which all contain 
anthraquinone derivatives, and particularly emodin, a trioxymethyl 
anthraquinone, 

OH CH 3 OH CH 3 



r-CO— j 

CO— ' 



-CO— 

-co— 



OH 



\/ 



OH, 



and, in still larger amounts, substances which are mostly glucosidal 
in nature, and from which, by hydrolysis or oxidation, different oxy- 
methyl anthraquinones are formed in the intestine (Tschirch x ) . These 
active emodins are formed by hydrolytic cleavage of the glucosides 
of senna, rhubarb, and the different species of Frangula, and by 
cleavage and oxidation of certain constituents of aloes. 

The oxyanthraquinones possess the power of electively exciting 
peristaltic movements of the large intestine, while they do not appear 
to produce any effect on the small gut. Magnus has shown that they 
exert their action locally in the Avail of the large intestine. Conse- 
quently, small doses cause only the evacuation of soft not completely 
concentrated masses of faeces, while large doses, which cause a stormy 
peristalsis of the colon, produce profuse watery diarrhoea. In any 
case they produce their effect after 8 hours or more, — i.e., they do not 
act until the drug has passed from the stomach into the colon. They 
are apt to produce more or less violent colicky pains and tenesmus. 

Among those organs which may be rendered hypera?mic as a result 
of irritation of the large intestine by drugs, particularly when the 
irritation and congestion are very pronounced, especial mention should 
be made of the female genital organs, which are innervated from the 
same nerve plexus, and which consequently may be reflexly influenced 
through the lower segments of the intestine. This action may, accord- 
ing to the circumstances, result in a desirable or undesirable increase 
in the menstrual flow of blood, and may also cause abortion in preg- 
nant patients. A number of drastic purgatives of this last-mentioned 
group, particularly aloes, are consequently used and abused for this 
purpose. 

Emodin is in part absorbed and passes into the urine, which may 
then take on a red color on the addition of an alkali. A certain por- 
tion is also excreted in the milk, imparting to it a cathartic action. 

Senna leaves, obtained from Cassia angustifolia, contain, besides 
1li is active glucoside, a resin with a very bitter taste, which may be 
removed by extraction with alcohol without impairing the cathartic 
power of the drug. From 0.5 to 2.0 gm. in the form of an infusion 
suffice for a mild cathartic effect, while 2.0-5.0 gm. act after 5-8 hours 



208 PHARMACOLOGY OF THE DIGESTION 

as a powerful purge. Senna leaves are the active ingredient of several 
official cathartic preparations, — for example, the compound licorice 
powder and the iiuidextract of senna. 

Among the Frangula species, Rhamnus frangula contains the 
largest amount of oxymethyl anthraquinone, about 5 per cent. When 
fresh, it contains emetic substances which disappear on keeping, and 
consequently this drug should be at least one year old. 

The widely used extract of cascara sagrada is prepared from 
Rhamnus purshiana. From the fruit of Rhamnus cathartica a laxa- 
tive syrup is prepared. 

Rhubarb, or Rheum, the root of Rheum officinale, contains,, besides 
the cathartic oxyanthraquinone compounds, a bitter and a large 
amount of tannic acid, the constipating action of which is alone evident 
when small doses — 0.1-0.3 gm. — are given, but after larger doses — 
1.0-5.0 gm. — the laxative action preponderates. 

Aloe, or aloes, the inspissated juice of the leaves of Aloe perryi, 
or socotrine aloes, and of Aloe vera, or Barbados aloes, both of which 
are official in the U. S. P., contains about 10-16 per cent, of aloin 
(G rone wold), a golden-yellow substance crystallizing in needle form, 
and considerable amounts of other anthraquinone derivatives 
(Tschirch-). 

The administration of from 0.1-0.3 gm. of pure aloin is followed 
after 8-10 hours by catharsis, this effect occurring whether the drug 
be administered internally or subcutaneously. In the latter case in 
man it is almost completely excreted into the large intestine, where, 
just as after internal administration, it is probably transformed by 
oxidation into a cathartic substance. As this oxidation is accelerated 
by the presence of metal salts, particularly by that of iron salts, the 
powerful cathartic effects of the piluke aloes et ferri are explained. 
According to Ellenberger and Baum, aloes powerfully stimulates the 
secretion of bile. 

The subcutaneous injection, best given in a 5-10 per cent, solution in 
formamide, causes considerable pain lasting for several minutes, but otherwise 
appears to be harmless (H. Meyer, Balster). 

In the rabbit aloes does not act as a cathartic, and when subcutaneously 
injected it causes serious damage to the kidney (Brandenberg) . 

In addition to these drugs of vegetable origin, there are certain 
synthetically manufactured anthracene derivatives which have proved 
themselves to be useful cathartics. The knowledge that phenolphtha- 
lein acts as a cathartic is due to an accidental observation made by 
v. Vamossy. 

PnENOLPIITIIALEIN, 



C 6 H 4 (OH) 2 =C CO, 

\c 6 H 4 / 



CATHARTICS ACTING ON LARGE INTESTINE 209 

is a yellowish-white crystalline powder, hardly soluble in water, but 
soluble in olive oil in the proportion of about 2 per cent. With alka- 
lies it forms red, readily soluble salts, which, when injected subcu- 
taneously, cause violent irritation of the tissues, but which, when 
administered intravenously, are very slightly poisonous. Phenol- 
phthalein itself, when injected subcutaneously dissolved in oil, readily 
causes evacuation of the bowels without causing local irritation. 

PhenoltetrachlorphtJialein, when injected subcutaneously (0.4 gm. 
in 20.0 gm. of oil), acts much more certainly, and the action persists 
for a number of days {Abel and Rowntree) . 

BIBLIOGRAPHY 
Abel and Rowntree: Journ. of Pharmacol, and Exp. Ther., 1909, vol. 1, p. 2. 
Balster: Diss., Marburg, 1890, here lit. 
Brandenburg: Diss., Berlin, 1893, here lit. 

Ellenberger u. Bauni: Arch. f. wiss. u. prakt. Tierh., 1898, vol. 25, p. 87. 
Gronewold: Arch. d. Pharm., 1890, vol. 228, p. 115. 

Magnus: Ergebn. d. Physiol., 1903, and Pfliiger's Arch., 1908, vol. 122, p. 251. 
Meyer, H.: Arch. f. exp. Path. u. Pharm., 1890, vol. 28. 

Stierlin: Miinchn. med. Woch., 1910, vol. 27. X-ray observations in man. 
'Tachirch: Arch. d. Pharm., vol. 237, 1899; vol. 238, 1900; Pharm. Post, 1904, 

Xos. 17-19, here lit. 
■Tsehirch: Sehweiz. Woch. f. Chem. u. Pharm., 1904, vol. 42, No. 35. 
v. Vamossy: Ther. d. Gegenw., 1902, p. 201. 

Sulphur. — One of those substances which normally stimulate the 
peristalsis of the large intestine is sulphuretted hydrogen (v. Bokay), 
which is formed in small amounts in the large intestine from the cell 
detritus and other substances containing sulphur. The amount of 
sulphuretted hydrogen formed here can be markedly increased by 
the administration of sulphur, for sulphur, in finely divided form, is 
reduced not only by bacteria but also by the direct action of certain 
proteids, particularly by the proteids present in the mucous mem- 
brane of the large and small intestine (Heffter), and this reduction 
occurs both in the acid-reacting contents of the small intestine and in 
the alkaline ones of the large gut. On the other hand, the gastric 
mucous membrane does not contain substances which reduce sulphur. 
Consequently, when sulphur is administered, it is not changed in the 
stomach and produces no action there, but, starting in the small 
intestine and all the way down through the large intestine, it is trans- 
formed little by little into sulphuretted hydrogen, which stimulates 
the peristalsis. 

As the sulphides of the alkalies have a caustic and destructive 
action on the tissues, this cathartic effect was formerly attributed 
to an irritation caused by them, but these salts are not formed in the 
intestine, as the high e;irbon dioxide tension of the intestinal contents 
i-oinplelely prevenfs llieif I'onnation. Consequently, even large doses 
of sulphur cause no appreciable caustic action or even, inflammatory 
irritation of the intestinal mucous membrane, and hence no diarrhoea 
but only soft stools result from its administration. 
14 



210 PHARMACOLOGY OF THE DIGESTION 

Eegensburger observed intestinal hemorrhages in dogs to which large doses 
(7.0 gm.) of precipitated sulphur had been administered, but it has not yet been 
determined whether these were the result of the caustic action of alkaline 
sulphides or were due to mechanical irritation produced by the fine particles 
of sulphur. It is also stated that sulphur has occasionally occasioned a fatal 
gastroenteritis in horses, but Hartwig, even after administering to a horse 
during 16 days as much as 3.0 kg. of sulphur, was able to produce only a chronic 
sulphuretted hydrogen poisoning, without any appreciable inflammation of the 
intestine (Frohner). 

Sulphuretted Hydrogen. — A portion of the H 2 S which is formed 
is absorbed, and a part of this is oxidized further, so that the oxidized 
sulphur of the urine is markedly increased (Krause) when sulphur 
is ingested. Another portion remains unchanged, and is excreted 
through the lungs and the skin. It is possible that, with the continued 
use of sulphur, certain mild symptoms of general H 2 S poisoning — 
such as headache, somnolence, muscular pains, and the like — may 
occur. However, certain authors (Wood) have attributed to the 
exhaled ILS a curative action on the bronchial mucous membranes, 
where it perhaps causes a hyperemia of the smallest blood-vessels and 
a stimulation of the bronchial secretion. Those springs containing 
sulphuretted hydrogen and alkaline sulphides have the reputation of 
being good expectorants and of producing curative effects in pulmonary 
catarrh. In veterinary practice the alkaline sulphides are employed 
in bronchial diseases. 

In Metallic Poisoning. — Sulphuretted hydrogen has also the repu- 
tation of being useful in chronic metallic poisonings, such as those 
produced by mercury, lead, etc., and it is possible that it decomposes 
the compounds of these metals, which are fixed in the tissues or which 
are excreted into the intestine and perhaps reabsorbed, and that it aids 
in bringing about the final elimination of these metals in the form of 
their insoluble sulphides. 

Sulphur is non-volatile, insoluble in water, soluble in ether, fats, 
etc. Sublimed sulphur (flowers of sulphur) is crystalline, while 
precipitated sulphur (milk of .sulphur) is amorphous and forms a 
very much finer and consequently more active powder. 

As Local Application. — Mixed with alkalies in pastes and salves it 
forms alkaline sulphides, and when these mixtures are applied to the 
skin these sulphides dissolve the horny structures, and consequently it 
is employed in the treatment of various skin diseases, such as psoriasis, 
pigmentation, etc. 

Calcium sulphide, obtained by introducing H 2 S into lime water, 
dissolves the hairs, and consequently may be used as a depilating agent. 

CARMINATIVES 

Carminative is the name given to a number of substances, to 

which are attributed the power of relieving distention, — i.e., the power 

of driving along gases which have collected in the alimentary canal 

and which are causing discomfort, Among such are chamomile 



OBSTIPANTS 211 

flowers and fennel seeds, which are so often given to little children, 
and the ethereal oils obtained from these and many other drags. Prob- 
ably these substances have some power of exciting intestinal peristalsis, 
but perhaps it is only the mild local anassthestic action of the ethereal 
oils which causes subjective relief of the discomfort. 

BIBLIOGRAPHY 

v. Bokay: Arch. f. exp. Path. u. Pharm., 1904, vol. 51, p. 175. 

Frolmer: Tierarztl. Arzneimittellehre, 1889,, p. 272. 

Heffter: Arch. f. exp. Pharm. u. Path., 1904, vol. 51, p. 175. 

Krause: Diss., Dorpat, 1853. 

Regensburger: Ztschr. f. Biol., 1876, vol. 12, p. 479. 

Wood, H. C: Therap. Gaz., April, 1887, Detroit, literature here. 

OBSTIPANTS, DRUGS WHICH RELIEVE DIARRHCEA OR CAUSE 
CONSTIPATION 

From the foregoing it is evident that drugs may produce consti- 
pation either by inhibiting peristalsis of the stomach and of the intes- 
tinal secretions. The direct inhibition of both these processes by 
opium or morphine, and under some conditions by atropine, has 
already been discussed. Indirectly they may be inhibited by pre- 
venting stimulation or irritation of the intestinal mucous membrane 
either mechanically or chemically, — i.e., primarily by withholding 
food, and secondarily by the administration of slimy substances of 
mucilaginous nature, such as gum arabic, decoctions of arrow-root, 
marshmallow-root, etc., which markedly interfere with chemical, and 
to some extent also with mechanical, irritation of the gastric and intes- 
tinal mucous membranes. Such an effect is also produced by the 
secretion of a large amount of a viscid mucus, containing large 
quantities of mucine, this being the natural protective reaction of the 
mucous membrane when chemically irritated. 

If a reflex frog be suspended so that the hind legs hang in an acid solution 
of just sufficient concentration, the legs are drawn up after a few seconds, but 
if this solution contains colloid substances, such as gum arabic, gelatin, or the 
like, this reflex movement docs not occur at all, or only very much later. In 
a similar fashion it is possible to demonstrate, on exposed nerves, raw surfaces, 
or other irritable tissues, the protective action. of slimy substances against chemi- 
cal irritants, — i.e., against the rapid penetration into the tissues of chemical 
substances (Tappeiner). 

Colloids, such as thin paste of starch or solution of vegetable slime, 
markedly retard the absorption of water and of substances, such as 
morphine or chloral, in watery solution ; but they do not cause — and 
in Eact they often check — diarrhoea, because peristalsis is slowed and 
consequently the fluid masses do not reach the large intestine. 

Finely divided insoluble substances, such as suspensions of talcum * 

• Debove [Progrto m4d. t 1883, No. 24) recommends for this purpose 200- 
600 gm< of talcum in milk. 



212 PHARMACOLOGY OF THE DIGESTION 

crcoline (Stumpf, Gorner, Levy), or insoluble salts, act in a similar 
fashion, covering 1 the surface of the mucous membrane with a thin 
coating and protecting it to a certain degree against the action of 
chemical agents. 

Charcoal. — Mention should here be made of the protective action 
of finely powdered charcoal (either animal or wood charcoal) and its 
power of interfering with absorption. This substance possesses in a 
very high degree the power of absorbing substances dissolved or sus- 
pended in finely divided form in water, a property which is widely 
used in chemistry and in technical manufactures as a means of 
decolorizing fluids. According to Wiechowski, many poisons, such as 
phenol, strychnine, morphine, bacterial toxins, etc., are so completely 
absorbed and persistently retained by charcoal, when it is taken in 
sufficient amounts, that these mixtures of poison and charcoal are abso- 
lutely non-toxic, either in the alimentary canal or when injected sub- 
cutaneously. In accordance with this, it may be expected that if 
charcoal (10.0-30.0 gm. and more) be administered, it will combine 
with poisons or irritating substances, or even with bacteria which may 
be present in the alimentary canal, and will thus render them harm- 
less, particularly if, by the subsequent administration of a cathartic, 
the charcoal with its absorbed poison be rapidly removed from the 
intestine. 

BIBLIOGRAPHY 

Gi3rner: Miinchn. med. Woch., 1907, No. 48. 

Levy: Die Bolustherapie, Diss., Freiburg, 1908. 

Stumpf: Ueber ein zuverl. Heilverf. bei der Cholera, Wurzburg, 1900. 

Tappeiner: Miinchn. med. Woch., 1899, No. 1230, p. 39; Arch, de pharmacodyn., 

1902, vol. 10, p. 67. 
Wiechowski: Fortschr. d. Med., 1909, No. 13. 

ASTRINGENTS 

Finally, the astringents act in a similar but more complicated 
fashion. These are substances which form with the proteid constitu- 
ents of the cells and of the secretions more or less stable colloid com- 
pounds, which are insoluble in neutral or weakly acid media. The 
chief ones are the various tannic acids, certain metallic salts, and 
calcium hydroxide. 

The more viscid and less soluble these colloid compounds are the 
more decidedly will they harden the surfaces on and in which they are 
formed, and consequently the more effectively will they prevent their 
own further penetration and that of other substances into the deeper- 
lying protoplasms and cells. 

They act in a similar fashion to the membrane formed in the wall 
of a diffusion cell by precipitation of ferrocyanide of copper, which 
renders these cells impermeable to substances in solution. Conse- 
quently, with the true astringents coagulation and the resulting death 
and destruction to the protoplasm are limited exclusively to the most 



ASTRINGENTS 213 

superficial layers of the tissues, which, are, as it were, tanned, and 
which form a protective coating against chemical, bacterial, and even 
against mechanical action, and thus protect against all sensory and 
inflammatory irritation. At the same time the secretory activity of the 
superficial glands which come in contact with the drug are diminished 
(Schiitz), and the exudation of fluid from Avounds or granulation 
tissues is stopped. 

Finally, astringents also bring about changes in the superficial 
capillaries and arterioles, whose walls become less permeable to the 
plasma and leucocytes, because the cement substance between the 
endothelial cells is rendered less permeable, while at the same time 
the circular muscular fibres contract and the vessels are narrowed 
as a result of the coagulation of their proteids (Heinz) . The tissues 
consequently become, at least in their most superficial layers, more 
ancemic, firm, and dry, and less sensitive. These are all effects which 
counteract swelling, redness, active secretion, and irritability of in- 
flamed tissues. Consequently, astringents are employed in inflamed 
wounds of mucous membranes as a means of relieving these conditions, 
and particularly in the treatment of catarrhal inflammation of the 
gastric and intestinal mucous membranes. 

Caustic Actions. — When astringents are at the start applied in con- 
centrated solution to a mucous membrane or to granulation tissues, 
they not only coagulate the most superficial layer, but, before the 
protective layer has had time to form, they penetrate deeper and 
cause the destruction of the deeper tissues. In such case they may 
produce considerable caustic effects, the degree and depth of which, it 
is clear, will depend on the diffusibility and solubility of the drug, 
and also on the chemical character of the drug itself as well as on that 
of the combination formed between it and the constituents of the 
tissues. If the eschar formed is not firm and tenacious but is soft or 
even fluid, it opposes no resistance to the further penetration and 
deeper action of the drug. Consequently, if a caustic substance 
possesses a strong chemical avidity for the body tissues (with the 
caustic metal salts it is chiefly the acid components which exhibit 
such avidity), it may, even in the low concentrations, produce con- 
siderable destruction of the tissues. Such more extensive destruction 
and death of the tissues will in this case, as always, cause an inflam- 
matory reaction, with dilatation of the capillaries, etc., which will 
finally end with the casting off of the necrotic masses and the regenera- 
tion of new tissues. 

Tiii': tannins are a number of non-nitrogenous amorphous colloid 
substances, present in almost all plants, readily soluble in water, 
glycerin, and alcohol, and entirely insoluble in water-free ether, which 
all possess the properties of precipitating albumin, gelatin, and vege- 
table bases in neutral or weakly acid solutions, and of coloring iron 
salts dark blue or green. They are Aveak acids, chiefly anhydrides 



214 PHARMACOLOGY OF THE DIGESTION 

and condensation products of different dioxy- or trioxybenzoic acids, 
particularly of gallic acid, which is formed when they undergo hydro- 
lytic cleavage under the influence of alkalies or ferments. While gallic 
acid gives the above-mentioned ink reaction with iron salts, it pre- 
cipitates neitlier albumin nor gelatin, and consequently is ivithoiit 
astringent action. 

Tannin, or tannic acid, is a yellowish powder obtained from nut- 
galls. It possesses an astringent taste and acts as an astringent in the 
above-described fashion, and, under certain conditions, may produce 
a superficial caustic effect. It may be used as an astringent appli- 
cation to all accessible mucous membranes or granulating surfaces, — 
for example, as a gargle or local application, in %-l per cent, solu- 
tion, in inflammation of the throat. 

Action in Alimentary Canal. — It is not well adapted for oral 
administration in the treatment of intestinal catarrh, because it 
produces its astringent effects chiefly on those tissues with which it 
first comes in contact, — namely, the gastric and duodenal mucous 
membranes, — and thus disturbs the appetite and digestion, and be- 
cause in the small intestine it undergoes hydrolytic cleavage and 
absorption, and consequently does not pass far enough down in the gut. 

Reputed Action after Absorption. — Gallic acid after absorption is almost 
completely combusted, but a small portion is excreted in the urine, either unaltered 
or in conjugation with sulphuric acid (Morner). Tannic acid itself or as an 
alkaline tannate does not pass into the urine; this is quite evident from the fact 
that any human urine which contains no albumin, whether acid or alkaline, 
forms an insoluble precipitate with tannic acid, even in the proportions of 
1 : 100,000. This same precipitate is also formed on the addition of tannin to 
the clear urine which is passed after ingestion of tannin (Rost 1 ). From these 
facts it is probable that, during or before its absorption by the intestinal 
mucosa, tannic acid is completely transformed into gallates of the alkalies, 
which possess no astringent properties. Consequently, an astringent or styptic 
effect in the lungs, kidneys, etc., cannot result from the oral or any other 
administration of tannin. 

Drugs Containing Tannin.- — When it is desirable that tannic acid 
reach the lower portions of the intestine, drugs are used which contain 
tannin inclosed in cellulose or in mucilaginous or other substances 
which protect it from too rapid solution and absorption. Such drags 
as rhatany, krameria, quercus alba, kino, etc., in the form of their 
extracts or decoctions, fulfil this indication. 

The large amounts of tannin present in many drugs which are used for 
quite different indications often produce undesirable effects, as is the case with 
extracts of calisaya or pomegranate-root bark. Radix ipecacuanhae, which we 
have already studied in the section on emetics, also contains large amounts of 
tannic acid, and it is probable that it is for this reason that it is used in the 
treatment of dysentery [? — see p. 182. — Tb.] 

Tannic Acid Compounds. — The desirable effects, however, are 
much more certainly and completely obtained by the administration 
of synthetically manufactured tannic acid compounds in which the 
tannic acid is firmly combined. These are almost tasteless powders, 



ASTRINGENTS 215 

which produce no astringent effects in the mouth or in the stomach, 
but which are gradually dissolved in the alkaline intestinal juices, 
"with the liberation of tannin in an active form. 

Tannalbin is such a compound, and is a tannin albuminate con- 
taining about 50 per cent, of tannic acid, which is rendered resistant 
to gastric digestion by heating to 110-120° C. (Gottlieb). This is 
gradually broken up by the pancreatic juice, and consequently exerts 
its action throughout the alimentary canal as far down as the colon 
and rectum. Its dosage is 1.0-2.0 gm. several times daily. 

Tannigen. — Another is tannigen, or diacetyl tannin, a yellowish- 
gray powder insoluble in neutral and acid fluids, with a mild acid 
taste, which contains about 85 per cent, of tannin. It is dissolved by 
weak alkalies, such as the carbonates, borates, etc., and, in such solu- 
tions, precipitates albuminates and gelatin. When given in rather 
large doses (0.5-4.0 gm.), it passes through the bowel down into the 
large intestine, where it may be found in part as unchanged tannigen 
but in part in the form of tannic acid ( H. Meyer u. F. Midler, Bost 2 ) . 

Tannocol, a compound of tannic acid with gelatin, containing about 
45 per cent, of tannin, and tannoform, a condensation product of tan- 
nin and formaldehyde, are substances with the same general properties. 

Coto. — In this connection mention may be made of coto-bark decoctions, 
which are employed, particularly in Italy, as curative agents in diarrhoea. The 
active constituents of this bark is not a tannin, but a very irritant bitter, 
cotoin, which is employed in doses ranging from 5.0-50.0 mg. Very little is 
known concerning its action on the intestinal mucous membrane. 

BIBLIOGRAPHY 

Gottlieb: Deut. med. Woch., 1896, No. 11. 

Heinz: Virchow's Arch., 1889, vol. 116. 

Meyer, H., u. F. Miiller: Deut. med. Woch., 1894, No. 31. 

Morner: Ztschr. f. phys. Chem., 1892, vol. 16, p. 255. 

1 Rost: Sitz.-Ber. Ges. Bef. d. ges. Naturw. Marburg, March, 1898. 

2 Rost: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 346. 

Schiitz: Arch. f. exp. Path. u. Pharm., 1890, vol. 27. 

METALLIC SALTS 

Of the astringent metallic salts only those are suitable for the 
treatment of inflammation of the gastric and intestinal mucous 
membranes which neither cause vomiting nor readily produce caustic 
effects on the mucous membranes. These requirements are best met 
by the insoluble 

Bismuth subnitrate, the dose of which is 0.2-1.0 gm. or more 
several times a day. It forms on the mucous membrane a firmly 
adhering coating (?Tr.), tonghenin.tr and protecting it and diminish- 
ing its secretory activity. Unless the mucous membrane is eroded, 
bismuth subnitrate La no1 absorbed, and consequently as large amounts 
as ono desires may be given without danger of poisoning by absorp- 
tion of the metal. This salt is to-day often used by rontgenologists 



216 PHARMACOLOGY OF THE DIGESTION 

for the purpose of observing or photographing the stomach and intes- 
tine and their movements. 

Danger of Nitrite Poisoning. — However, such employment carries 
with it some danger from another source, for abnormally active bac- 
terial fermentation in the large intestine reduces the nitrate to a 
nitrite, which may be absorbed in considerable amounts. As nitrites 
are poisons to the blood, very small amounts of which may cause 
death, this danger should be avoided, and, consequently, in rontgeno- 
logic work the basic bismuth sulphate or chloride or oxide should be 
substituted for the subnitrate. 

Cattle and deer may suffer from the same toxic action on the blood if they 
consume considerable amounts of saltpetre spread upon the fields as a fertilizing 
agent. If sodium nitrate is not rapidly absorbed, but remains for a considerable 
time in the stomach, it may be reduced and transformed into a lethal poison 
(Bohmc, E. Meyer, Hoffmann u. Bennecke) . 

In the large intestine bismuth subnitrate and other bismuth salts 
combine with H 2 S and form the deep-black bismuth sulphide, and in 
this fashion one of the effective stimuli of peristalsis is removed and 
consequently peristalsis becomes less active (v. Bokay). 

Other basic insoluble bismuth compounds used in medicine in the 
same fashion as the subnitrate are the subgallate and subsalicylate, 
the former of which carries the commercial name of dermatol. 

Lead acetate, or sugar of lead, is soluble in water, and conse- 
quently should be employed only in weak non-corroding concentrations. 
The dose is 0.1 gm. ( !) per dose, 0.3 gm. ( !) per diem. It is a power- 
ful astringent, constricting the vessels quite markedly, and is slowly 
absorbed, and, therefore, when used for a long time may cause poison- 
ing. This salt could be entirely dispensed with for internal use, and 
the same is true of 

Alum, which, although a good astringent and one which when 
absorbed does not cause any poisoning, readily causes gastric irri- 
tation or vomiting, even when administered in small amounts. 

Silver nitrate has also been much used as an astringent in the 
stomach and intestine. As a large part of it is changed in the stomach 
into silver chloride, which is insoluble in water containing hydrochloric 
acid, but which is somewhat soluble in the presence of chlorides of the 
alkalies, it is probably entirely ineffective in the stomach. [With this 
sweeping statement clinicians will hardy agree. — Tr.] When adminis- 
tered by mouth, however, there can be little doubt that silver nitrate 
never reaches the lower portion of the intestine in an active form, for 
it is rapidly reduced to metallic silver by organic substances present 
in the stomach and intestine. 

A small portion is absorbed probably as an albuminate and dis- 
tributed throughout the body by the lymph, where it is deposited in 
the various tissues in the form of a reduced metal (Fraschetti) . In 
this fashion the various organs — and, in man, especially the skin — 



LIME WATER 217 

are colored slate-gray, from which in other particulars no harm 
results. This condition is known as argyria. 

Calcium hydroxide, chiefly used as lime water, which contains 
0.15 per cent, of Ca(OH) 2 , forms insoluble soaps with the fatty acids, 
and thus toughens the lipoid constituents and the intercellular cement 
substances of the tissues, an action which may be aided by the mechani- 
cal protective action of the calcium carbonate which is formed on the 
surface of the mucous membranes. The very slight concentration 
of lime water renders it hnpossible for it to cause any corrosive effect, 
while its alkaline nature enables it to dissolve the tenacious mucus 
adhering to the inflamed mucous membranes and thus to produce a 
cleansing effect (Harnack). As an alkali, it can also neutralize harm- 
ful acids, such as are formed in the acid intestinal catarrh of nursing 
infants (Baudnitz). The constipating effects of lime water or of 
waters containing calcium are probably also due in part to the action 
exerted by the lime salts, after their absorption on the vegetative ner- 
vous system, the excitability of which they depress, and in part to their 
effects on the capillary vessels, the permeability of which they lessen 
(Chiari u. Frolilicli, Chiari u. JanuscJike) (see p. 495). 

BIBLIOGRAPHY 

Baudnitz: Prager med. Woch., 1893, No. 29. 

Bohme: Arch. f. exp. Path. u. Pharm., 1907, vol. 57, p. 441. 

v. Bokay: Arch. f. exp. Path. u. Pharm., 1887, vol 23, p. 209. 

Chiari u. FrShlich: Arch. f. exp. Path. u. Pharm., 1911, vol. 64, p. 214. 

Chiari u. Januschke: Arch. f. exp. Path. u. Pharm., vol. 65, p. 120. 

Fraschetti: Molesehott's Unters., 1895, vol. 15, p. 143. 

Harnack: Berl. klin. Woch., 1888, No. 18; 1889, No. 26. 

Meyer, E.: Miinchn. med. Woch., 1906, No. 53. 



CHAPTER VII 

PHARMACOLOGY OF THE REPRODUCTIVE ORGANS 

NERVOUS AND CHEMICAL CORRELATION 

Like those of the alimentary canal, the functions of the genital 
organs, with their glands and unstriated muscles, are controlled partly 
by manifold nervous reflexes and partly by the direct action of 
various stimulating substances which reach them in the blood stream. 
While formerly the relationship between the different functions of the 
genital organs with each other and with numerous other functions 
were attributed exclusively to central nervous influences, it has more 
recently been proved that the genital organs influence the development 
and function of distant tissues and organs chiefly by means of their 
internal secretions, — i.e., by chemical agents (hormones). 

The Ovaries. — Thus, the importance of the ovaries for the development of 
the other female sexual organs is well known. In animal experiments, after 
extirpation of the ovaries in young subjects the uterus and tubes remain rudi- 
mentary (Hegar, Kehrer), but, if the ovaries are transplanted under the skin, 
normal development of the uterus and tubes occurs (Halban). The connection 
between the periodic changes, which the uterine mucous membrane undergoes, 
and the associated changes in numerous bodily functions, are also, at least in 
part, due to the action of chemical substances which are formed as the ovum 
matures, for Knauer observed the occurrence of "heat" in animals in which 
the ovaries had been transplanted to other parts of the peritoneal cavity. 

Both the testicles and the ovaries form chemical substances, 
which exert an influence on other portions of the genital system and 
on many other parts of the body. This highly specialized tissue is 
very readily destroyed by the action of X-rays, so that the application 
of these rays leads to atrophy of testicles or ovaries, and thus to all 
the indirect results of a cessation of the function of these organs. 
In practice the ovaries are at times thus treated. The ovarian follicles 
appear to be very susceptible also to certain toxic substances at times 
present in the blood, so that, for example, sterility and retrogression 
of the pregnancy may be produced by injections of choline (v. Hippel 
and Pagenstecher) . 

It is this more or less sudden cessation of the ovarian influences 
which causes the manifold disturbances following ovariotomy and 
the menopause. Reliable observations indicate that they may be 
favorably influenced by the internal administration of ovarian tissue 
(Chrobak, Landau). 

Other functions connected with the function of reproduction, as 
well as those of the reproductive organs, are also influenced by the 
internal secretion of the germ-glands. Examples of this are as fol- 
lows : The callosities on the thumb and certain muscles of the forearm 
218 



NERVOUS AND CHEMICAL CORRELATION 219 

of the brown frog hypertrophy at the rutting season. This does not 
occur in castrated frogs if a piece of testicle is put into the dorsal 
lymph-sac and gradually absorbed (Nussbaum). The complete de- 
velopment of all the secondary sexual characteristics is also influenced 
by the germ-cells, as are the growth of bone and the general metabo- 
lism. As far as the effects of these internal secretions on other func- 
tions are definitely known, they will be discussed elsewhere, but we 
are far from possessing anything like a complete knowledge of the 
internal secretions or of their actions. For this reason, their thera- 
peutic employment with clear indications is at the present time ex- 
tremely limited. 

BIBLIOGRAPHY 

Chrobak: Zentralbl. f. Gyn., 1896, vol. 20. 

Halban: Monatsschr. f. Geburtsh. u. Gyn., 1901, vol. 12, p. 496. 

Hegar: Beitr. z. Geburtsh. u. Gynakol., 1903, vol. 7, p. 201. 

v. Hippel u. Pagenstecher : Miinchn. med. Woch., 1907, No. 10. 

Knauer: Arch. f. Gvn., 1900, vol. 60, p. 322. 

Landau, M.: Berl. med. Woch., 1896. 

Nussbaum: Pfliiger's Arch., 1909, vol. 129, p. 110. 

Erection. — Among the secondary sexual characteristics which first 
become evident at puberty, and which depend on the internal secre- 
tions of the testicles, is the development of a specific sensibility of 
certain lower nervous centres, which are involved in the function of 
reproduction. The complicated reflexes which induce erection are 
primarily dependent on psychic processes, and may be excited or in- 
hibited from the cerebral cortex, or may, on the other hand, result 
from peripheral stimuli. 

Yohimbin, an alkaloid contained in the yohimbe bark (W. Africa), 
apparently is able to increase the excitability of the centres for erec- 
tion in the lumbar cord, even in doses which do not affect the excita- 
bility of other centres there, such as that for the patella reflex (Fr. 
Mutter). At the same time it causes a local dilatation (by direct 
action on the vessel walls) in various vascular systems, but most espe- 
cially so in the vessels of the penis, and there results a marked increase 
in the amount of blood flowing out of the dorsal vein of the penis. 
[t is probable that other reputed aphrodisiacs favor erection by local 
vasodilating actions. The aphrodisiac effects of cantharidin and cer- 
tain other drugs, which are excreted by the kidney and set up an 
inflammatory irritation of the urogenital tract, are probably due to 
such sensory irritation and its accompanying vasodilatation. 

MAMMARY GLANDS 

A most interesting nervous and chemical correlation exists between 
the genital system and the function of the mammary glands, the 
growth of which in the female at puberty is doubtless due to a stimulus 
coming from the ovaries. 



220 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

Observations on animals have shown that the development of these 
glands is retarded after double oophorectomy, but proceeds quite nor- 
mally after successful transplantation (Foges, Kramer). The changes 
in the breast during pregnancy also occur independently of any ner- 
vous influences, for after successful transplantation of these glands 
their growth and active secretion have been observed in pregnant 
guinea-pigs (Eibbert). The hormone here appears to be a product 
of the fetal metabolism, for injections of fetal extracts excite hyper- 
trophy of the mammary gland in virgin animals (Starling and 
Claypon, Foa, Biedl). 

Lactagogues. — The inauguration of the lacteal secretion after 
delivery is likewise in part due to chemical stimuli, and apparently 
also in part to the cessation of an inhibitory influence which is exerted 
by the fetal substances which stimulate the growth of these glands 
(D'Errico). Very recently several investigators (Basch, Lederer 
and Pribram) have demonstrated the presence of galactagogue sub- 
stances in placental extracts, injection of which increases the milk 
secretion of goats. 

This secretion, moreover, may be influenced by numerous nervous 
influences, and especially by manifold reflexes, among which those 
from the genital organs and that from suckling are especially impor- 
tant. The innervation of the lacteal glands must, however, be entirely 
different from that of the other true glands, for even such a typical 
stimulant of glandular activity as pilocarpine produces no effect on 
the milk secretion (Hammerbacher) . "While, generally speaking, this 
secretion depends on the general state of nutrition, it can in no way 
be influenced by feeding special food-stuffs, nor has it been proved that 
it can be influenced by pharmacological agents. Of true medicinal 
galactagogues there are none, but, on the other hand, it is claimed that 
the secretion of milk mav be distinctly lessened by the administration 
of EX 

Elimination of Drugs in the Milk. — That many foreign substances may- 
pass into the milk lias been definitely established, the following having been 
demonstrated in human milk after their medicinal administration: iodine, bro- 
mine, salicylic acid, antipyrine, arsenic, and mercury (Bxicura) , while alcohol, 
morphine, and atropine have been found in the milk of animals. However, only 
very small amounts of such foreign substances are present in the milk. 

The excretion of antitoxins through the lacteal glands (Ehrlich) 
appears to be of great significance in connection with the transference 
of protective substances to the suckling. 

BTBLIOGKAPHY 

Basch: Monatsh. f. Kinderheilkunde, 1909, vol. S. 

Biedl: Innere Sekretion, 1910, p. 343. 

Bucura: Zeitschr. f. exp. Path. u. Ther., 1907, vol. 4, p. 398. 

Ehrlich: Zeitschr. f. Hyg. u. infektionskrankh., 1892, vol. 12. 

D'Errico: La Pediatria. 1910, No. 4. 

Foa: Arch, di Fisiol., 1909, vol. 5. 



UTERINE MOVEMENTS 



221 



Foges: Zentralbl. f. Physiol., 1905, vol. 19, p. 233. 
Hammerbacher : Pfliiger's Arch., 18S4, vol. 33, p. 228. 
Kramer: Miinchn. med. Woch., 1906, No.. 39; 1909, No. 30. 
Lederer u. Pribram: Pfliiger's Arch., 1910, vol. 134, p. 531. 
Miiller, Fr.: Arch, intern, de pharm. et de ther., 1907, vol. 17, p. SI. 
Ribbert: Fortschritte d. Medizin, 1S98, vol. 7. 

Starling and Clavpon: Proc. of the R. S., 1905, p. 505; Ergebnisse d. Phvsiol., 
1906, pp. 6-64. 

THE PHARMACOLOGY OF THE UTERINE MOVEMENTS 
Although the same pharmacological principles hold good for the 
treatment of disease of the mucous membranes of the genital tract as 




Bladder 
Hypouastric plexus 
Fia. 10. — Sympathetic nerves, red; nervus hypogastricus, blue. 



for the other mucous membranes (see Pharmacology of Inflammation, 
p. 481, and Disinfection of the Mucous Membranes, p. 508), the pharma- 
eology of the uterine movements deserves special attention. 

Like the intestine, the uterus in situ or when isolated manifests 
pendulum movements and peristaltic contractions, and these phe- 
nomena may be studied for hours in the perfused uterus (Kurdinow- 
8ki ' i or in one surviving in Ringer's solution which is kept saturated 



222 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

with oxygen (Kehrerh 2 ). It is thus evident that this organ contains 
within itself the factors necessary for its automatic contractions, 
which vary according to the state of the uterus, occurring most fre- 
quently in the early stages of pregnancy, and later becoming less fre- 
quent but more powerful, being separated by long periods of inactivity. 

Innervation. — The uterine movements, like those of other organs contain- 
ing smooth muscle, are regulated by the central nervous system, receiving from 
it motor and inhibitory impulses through the sympathetic and probably also 
through the sacral autonomic nerves (see Fig. 10). The Nervus pelvicus 
(erigens), whose fibres arise from the second, third, and fourth sacral roots, 
supplies the rectum, anus, bladder, and the external genitals, and probably also 
the uterus, with sacral autonomic fibres, while the hypogastric nerve, which 
arises from the inferior mesenteric ganglion, and the spermatic nerve, from the 
spermatic ganglion, belong to the true sympathetic system proper. The uterine 
ganglion lies more peripherally in the neighborhood of the cervix. Much uncer- 
tainty still prevails as to the iniluence exerted on the uterus by these different 
nerves, for not only is the anatomical arrangement complicated, but, in addition, 
their different behavior in different species renders it most difficult to determine 
definitely their physiological significance. 

Effects of Epinephrin and of Stimulation of the Sympathetic. 
— According to Langley and Anderson, in the cat stimulation of the 
hypogastric at first produces chiefly stimulation Of the inhibitory 
fibres, while in the rabbit it causes excitation from the start. Epi- 
nephrin acts on the uterus quite analogously to the stimulation of 
these sympathetic fibres, causing in the cat first inhibition and then 
excitation, but in the rabbit immediate excitation. 

Effects of "Autonomic" Drugs and of Stimulation of Autono- 
mic Nerves. — The influence of the nervus pelvicus is still more uncer- 
tain, for this nerve carries vasodilating nerves to the uterus (v. Basch 
and Hofmann), and stimulation of its trunk excites uterine contrac- 
tions {Rohrig, F. Kehrer), which last effect, according to Langley and 
Anderson, is due only to its containing some fibres from the hypo- 
gastricus, which join it deep down in the pelvis. Pharmacological 
observations, however, indicate that the pelvic nerve also contains 
•motor nerves, which actually come from the sacral autonomic system, 
for that group of drugs which in general act on the autonomic nerve- 
endings produce a decided effect on the uterus. Thus, pilocarpine 
and physostigmine excite violent uterine contractions, which may 
become tonic in character, while here, as in the intestine, atropine 
in small doses causes excitation and in large doses cessation of the 
movements of the uterus (E. Kehrer 1 ) 2 ). 

DIFFERENT REACTION OF THE GRAVID AND NON-GRAVID UTERUS 
Nicotine produces different effects in different species of animals, 
and also in the gravid and non-gravid uterus, primarily inhibiting 
and later exciting the empty organ and immediately exciting the 
gravid one. Epinephrin, too, exhibits a similar difference in the 
effects produced by it in the gravid and non-gravid uterus 



UTERINE MOVEMENTS 223 

{Dale, E. Kehrer 1 ^). The difference in the reactions of the 
gravid and non-gravid uterus to these drugs is in accord with 
the influence of sympathetic stimulation in the two conditions 
for it has been found that in the cat stimulation of the hypogastric 
nerve inhibits the non-pregnant uterus but excites the pregnant one 
(Langley and Anderson, Dale). It would, therefore, appear that 
the stretched muscle-fibres of the gravid uterus are more susceptible 
to all exciting agents than those of the empty organ (Cushny). This 
is in accord with clinical experience. 

Hypophysis Extracts. — Recently it has been found that the 
extract made from the infundibular portion of the hypophysis, pitui- 
trin, excites maximal contraction of the rabbit's uterine muscle and 
renders it more susceptible to motor stimuli (FranM-Hochwart and 
Frohlich). 

Pilocarpine and Nicotine. — The above-discussed action of pilo- 
carpine is the ground for its employment as an oxytoxic (Brennecke, 
Kleinivdchter), while the excitation of the uterine contractions pro- 
duced by nicotine is of toxicological interest on account of the occa- 
sional unjustifiable employment of an infusion of tobacco as an 
abortifacient. Besides those already mentioned, numerous other drugs 
act on the terminal nervous mechanism in the uterus. Among these 
is quinine, which is much used to strengthen lagging pains (Backer, 
Maurer, Conitzer), excites contractions in the surviving uterus and 
hence must act peripherally (Kurdinowski, 2 E. Kehrer 3 ). Small 
doses of morphine excite (while large ones inhibit) uterine contractions 
(E. Kelircr 4 ). Bearing in mind the difference in individual suscepti- 
bility to morphine, this difference in the effects of small and large 
doses accounts for the contradictory clinical views concerning the 
effect of morphine on parturition. In this connection it is of interest 
that scopolamine appears not to affect the uterine contractions 
appreciably. 

DRUGS WHICH INFLUENCE THE UTERINE CONTRACTIONS CENTRALLY 
OR REFLEXLY 

In addition to being affected by these peripherally acting agents, 
the uterine contractions may be influenced by many agents which act 
on the central nervous system (centres in the lumbar cord), as, for 
example, by anaemia or asphyxia, both of which strengthen the com 
tractions. These spinal centres are, moreover, under the control of 
higher centres, some of which are situated in the cerebral cortex and 
may l><' influenced by reflexes of the most varied origin, especially from 
the nasal mucous membrane (Fliess, Schiff). Toxicologically it is 
important to remember that, simultaneously with peristalsis, uterine 
contractions may .be reflexly excited by chemical irritation of the 
intestinal mucous membrane (E. KrJircr 4 ). It is for ibis reason that 
d rustic purgatives — for example, aloes — may excite uterine contrac- 



224 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

tions and cause abortion, not only by causing hyperemia of the pelvic 
organs but also by causing reflex stimulation of the uterine contrac- 
tions. The same holds for other abort if acients, such as the ethereal 
oils of Tanacetum vulgare (tansy), Thuja occidentalis (arbor vitce), 
Taxus baccata (yew tree), Juniperus sabina, etc., which all cause 
gastro-enteritis and at the same time may cause abortion. The extent 
to which specific effects on the uterus also contribute to this result 
has not yet been settled. Why uterine hemorrhages, abortions, and 
miscarriages occur after large doses of salicylic acid is entirely 
unknown (Binz). 

BIBLIOGRAPHY 

Biicker: Deut. med. Woch., 1905, p. 417. 

v. Basch u. Hofmann: Wiener med. Jahrbiicher, 1877, p. 465. 

Binz: Berl. klin. Woch., 1893, p. 985. 

Brennecke: Berl. klin. Woch., 1880, p. 122. 

Conitzer: Arch. f. Gyn., 1907, vol. 82, p. 349. 

Cushny: Journ. of Physiol., 1906, vol. 35, p. 1. 

Dale: Journ. of Physiol., 1906, vol. 34, p. 163. 

Fliess: Die Bezieh. zw. Nase u. weibl. Geschlechtsorgan, Leipzig and Wien, 1897. 

v. Frankl-Hochwart u. A. Frohlich: Wiener klin. Woch., 1909, No. 27. 

Mvehrer, E.: Arch. f. Gyn., vol. 81. 

'Kehrer: Arch. f. exp. Path. u. Pharm., 1908, vol. 58, p. 366. 

3 Kehrer: Arch. f. Gyn., 1906, vol. 81. 

4 Kehrer: Arch. f. Gyn., 1910, vol. 90, p. 169. 

Kehrer, F. : Beitr. z. vergl. u. experim. Geburtskunde, Giessen. 

Kleinwachter: Arch. f. Gyn., 1878, vol. 13, p. 280. 

1 Kurdinowski: Engelmann's Arch. f. Physiol., Suppl., 1904, p. 323. 

- Kurdinowski: Arch. f. Gyn., 1906, vol. 7S, p. 34. 

Langley and Anderson: Journ. of Physiol., 1895, vol. 19. 

Miiurer: Deut. med. Woch., 1907, p. 173. 

Rohrig: Virchow's Arch., 1879, vol. 76, p. 1. 

Schiff, A.: Chrobak's Festschrift, 1903, p. 374. 

In practice, ergot, hydrastis, and cotarnine, and quite recently 
epinephrin and pituitrin, are employed for the purpose of exciting 
or strengthening uterine contractions. 

ERGOT 

Ergot (Secale cornutum) is the sclerotium of the fungus Claviceps 
purpurea, which causes a fungous disease in various grains, especially 
in rye during wet seasons. 

In former times ergot caused very severe epidemics of ergotism, and 
even in recent decades such epidemics have occurred in many civilized 
countries. (1867-8 in East Prussia, 1894 in Nanterre, France, 1907-8 
in Hungary, and in numerous years in various districts in Russia.) 
When ergot is ground with the grain, as much as 6-10 per cent, may 
be present in bread and foods made from the flour, and even %-l per 
cent, is enough to cause poisoning. In epidemics two types of disease 
occur, a convulsive and a gangrenous type, one type or the other being 
usually the prevailing one in a given epidemic, although epidemics 
have been described in which one type alone was observed (Robert 1 ). 



ERGOT 225 

The varying clinical picture of spasmodic or convulsive ergotism starts with 
a feeling of numbness in the fingers, which spreads over the whole body; later 
gastro-intestinal disturbances, with vomiting and purging, develop, and still 
later the typical spasms. These consist in very painful tonic contractions of the 
muscles, occurring at intervals and affecting especially the flexors of the extremi- 
ties and leading to typical contractures. In addition, there may finally occur 
clonic epileptiform convulsions, which may last for hours. The contractures 
remain permanently, and with them serious disturbances of the nervous system, 
such as pseudo-tabes or imbecility. 

Gangrenous ergotism also often starts in the same way, with prickling 
and numbness of the fingers, vomiting and diarrhoea, and after some days the 
typical lesions of gangrene. In these the skin over the affected parts loses its 
natural color and turns black and blue, the epidermis is raised up over the 
gangrenous spots, and dry gangrene of whole toes and fingers may result, and at 
times also of the ears or nose. The development and limitation of the gangrene 
is at first accompanied by very severe pain, but later complete anaesthesia develops. 

During such epidemics abortions and miscarriages are often observed, and 
consequently as early as the 17th century ergot was employed as an oxytocic. 
On account of its abuse, the drug soon fell into disrepute, and its use was much 
opposed and was even forbidden at the end of the 18th century, but early in 
the 19th century it was re-introduced into therapeutics. 

Practical experience obtained from the use of ergot indicates a 
threefold action of the drug, — the first that of exciting spasms, which 
is responsible for the convulsive ergotism; the second that of causing 
gangrene, which is responsible for the gangrenous ergotism; and the 
third and most important, its action on the uterus. In addition, active 
preparations of ergot cause vasoconstriction and a rise in blood- 
pressure. In spite of many laborious investigations, for a long time 
little advance was made in determining which constituents of ergot 
were responsible for these different actions, but recent efforts have 
been more successful. 

Active Principles. — Extracts of ergot are mixtures of complicated 
and inconstant composition, from which there have been prepared 
at least three pure substances, which are concerned in its pharmaco- 
Logical actions. One of these, ergotoxin (Kraft, Barger, Carr and 
Dale 1 , 2 *), an amorphous alkaloid, exerts the specific characteristic 
action of ergot. In addition to it, ergot extracts contain at least two 
physiologically very active ptomaine-like bases, which are formed 
either by the metabolism of the fungus or by the actions of micro- 
organisms on organic mother substances (Barger and Dale M). 

Inactive Constituents. — Besides these three active ingredients, ergot contains 
a large number of less active substances, — for example, leucine ( Buchheim, Jiurgi'r 
and Dale), uracil, tetra- and pentamethylenediamine, betaine, and choline 
[Rielander) . As a means of recognizing the presence of ergot in bread and 
Hour, considerable interest attaches to sclcrcrythrin, a red coloring matter of 
;niil character, which, along with other coloring matters, occurs in the drug 
combined with Ca and \\<i. It passes readily from acidified water into ether 
and may !»■ readily identified chemically and spectroscopic^ ly. 

Ergotoxin. — According to a number of investigators (Kraft, Bar- 
ger, <'<irr;\i\(\ Pah '■-•), there is present in ergot a crystalline alkaloid, 
ergotinin, first prepared by Tanret. This lias no action on the uterus, 
bul is accompanied by its amorphous hydrate, hydro-ergotinin or 
15 



226 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

ergotoxin, which apparently is the most important constituent of the 
drug. According to Dale, when administered subcutaneously or intra- 
venously this substance causes contraction of unstriped muscle, espe- 
cially of the uterine muscle, a rise in blood-pressure due to vasocon- 
striction, and also the characteristic ergot gangrene. The rise in 
blood-pressure is due to peripheral action and is very persisting, 
but after large doses this primary excitation of the vasoconstrictor 
nerve-endings is followed by an elective depression of the pressor 
sympathetic nerves, so that the blood-pressure falls and can no longer 
be raised by epinephrin, but under these conditions is actually lowered 
by it (Dale's vasomotor paradox). 

Aqueous extracts of ergot also contain two very active bases, which 
in their actions closely resemble epinephrin, parahydroxyphenylethyla- 
mine (Barger and Dale 1 '-), formed from tyrosine in the mycelium 
of the fungus by bacterial action, which is a very powerful vasocon- 
strictor, and fi-imidazolylcthylamine [Barger and Dale 3 ), similarly 
formed from histidine, which even in enormous dilutions excites violent 
uterine contractions. 

Other Alkaloids. — Formerly the specific actions of ergot were attributed 
to various alkaloids ( Robert- ) and resinous substances combined with them 
(Jacobi). 

Among these alkaloids the substance known as cornutine for a time 
attracted considerable attention, but later investigations have shown it to be, 
not a pure substance, but a mixture of various alkaloids, among which is 
ergotoxin, and that it has little or no therapeutic activity. ' It is, however, 
possible that this mixture of alkaloids known as cornutine, and perhaps their 
decomposition products, which are present in ergot, are responsible for the 
convulsive actions of ergot, for it causes typical tonic and clonic convulsions 
and behaves like a typical convulsant. As, however, it is not always a con- 
stituent of ergot and as no one has yet succeeded in producing chronic poisoning 
in animals by its administration, its significance for convulsive ergotism is still 
uncertain (Hchmiedcberg) . Cornutine excites uterine contractions by an action 
on the central nervous system, but some observers have found it effective in 
surviving uterus, which may be explained by its containing ergotoxin. 

Resinous substances which are present in ergot, combined with inert alka- 
loidal substances, have also been considered as the constituents responsible for 
the specific effects of the drug. Among such are sphacelic acid (Kobcrt z ) 
and sphacelotoxin, which latter, although possessing no true acid properties, 
readily combines with other substances, forming, among other compounds, 
chrysotoxin and secalintoxin (Jacobi). According to more recent investigators 
{Kraft, Barger and Dale 4 ), these are not chemical entities, Dale claiming that 
the nitrogenous component of the mixture is identical with ergotoxin. Robert 3 
and Jacobi, from their observations on animals, believed that the poisonous 
resinous acids and their salts were the substance which caused the gangrene, 
but recently Kraft and Barger and Dale have attributed this effect to ergotoxin. 

Experimentally the gangrene is best produced in the cock's comb and in 
the pig's snout. It is due to a peculiar change occurring in the vessel walls, 
a hyaline thrombosis of the smallest arteries, which develops in the periphery 
as a result of the stasis resulting from the toxic contraction of the 



From this short survey of the more important points bearing on the 
chemistry of ergot and its constituents, it is evident that much uncer- 
tainty still obtains as to the chemical properties and the homogeneity 
of the various substances prepared from it, and also as to their 



ERGOT 227 

activity. In view of these contradictions especially, little may be 
maintained with certainty as to the chemical composition of the con- 
stituents which cause the specific effects on the uterus. 

There is no doubt, however, that this substance — or these substances 
— are readily extracted by water and less readily by alcohol. The fact 
that such difficulties have attended the efforts made to isolate the 
substance acting- on the uterus, and that repeatedly new substances 
have been described as the true active principle, is due both to the 
marked instability of the active substances and to the very active reac- 
tion of the uterus, especially when gravid, to various toxic substances, 
central excitants acting on the uterus through the centres while the 
sympathetic and autonomic poisons act on the nerve-endings in the 
uterus itself. In addition, the interpretation of experimental results 
is rendered still more difficult by the fact that the uterus may be 
affected by various reflexes and by such factors as asphyxia, in such 
fashion that it may appear that it is directly affected by a drug 
when this is not the case. 

Instability of the Active Principles. — As the substances acting* on 
the uterus so readily undergo change, the apothecary should renew 
his supply each year. [This is legally obligatory in Germany. — Tr.] 
Ergot is most active before the rye has ripened. When stored its 
specific (uterine) activity gradually diminishes, until at the end of a 
year it possesses only one-seventh to one-eighth of its original activity, 
and at the end of two years only one-fifteenth (E. Kehrer). The 
substance causing gangrene appears to be even more unstable, for the 
effect on the cock's comb, according to Robert and Grunfelcl, can be 
obtained only in the first few months following the harvest, being 
markedly weaker in November and having entirely disappeared by the 
following March. 

Physiological Assay. — This effect on the cock's comb (Kehrer), 
the action on the blood-pressure {Dale, Wood and Ilofcr), and the 
excitation of the surviving cat's uterus (Kehrer), have all been 
employed as methods of physiological assay. As these different effects 
are in part due to different constituents, it is evident that the results 
of the assay will vary with the method employed (Crony a and Hender- 
son . As ergot is chiefly employed for its effects on the uterus, the 
most rational assay method is that in which the cat's uterus is 
employed. 

It can be demonstrated that ergot extracts excite contractions in 
1 1n- uterus surviving in Ringer's solution, increased tone and strength- 
ening of the autonomic contractions resulting from ordinary doses, 
and tonic contractions from larger ones. This action is, therefore, a 
peripheral one, agreeing qualitatively with the effect of intravenous 
injection of active extracts oil uterine movements in the living animal. 
Ergotoxin mid B-imidazolylethylamim are tht only hen substances 



228 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

which have thus far been prepared in pure form and which produce 
this characteristic action. 

Vasoconstrictor Action. — Certain of the active principles of ergot 
also act on the vessel walls or on the vasomotor nerve-endings in them, 
and, therefore, active ergot extracts may raise the blood-pressure. 
This action is also a peripheral one, and appears to be due to ergo- 
toxin and hydroxyphenylethylamine. 

Therapeutic Employment. — In obstetrical practice ergot is no 
longer used to strengthen uterine contractions during labor, for the 
inconstant strength of its preparations renders the dosage uncertain, 
and, therefore, there is danger of causing tonic contraction of the 
uterus and death of the child; but, after delivery of the child and 
loosening of the placenta, it is generally used for the purpose of 
checking hemorrhage and to bring about a firm and lasting contraction 
of the uterus. The effects in checking hemorrhage under such con- 
ditions have been attributed to a contraction of the uterine vessels 
under the influence of the drug, but this is not strictly the case. 
However, the contraction of the uterine muscle, which is excited by 
ergot, itself acts to check bleeding, for the uterine vessels are enclosed 
in a mesh of uterine muscles, and when the muscles contract they 
are compressed so that the formation of thrombi is favored. This is 
the reason why ergot is so efficient in checking uterine hemorrhage, 
although its action on other hemorrhages is so uncertain. The stop- 
page of uterine hemorrhage could be attributed to a direct action on 
the vessels only on the hypothesis that only the uterine vessels are 
constricted and that no extensive vasoconstriction occurs elsewhere, 
for otherwise a general rise in blood-pressure would result and the 
checking of the hemorrhage would actually be rendered more difficult. 

Preparations. — In addition to powdered ergot, numerous other 
officinal and non-officinal preparations are employed. [In this coun- 
try the fluidextracts are almost exclusively employed. For practical 
purposes an aseptic, physiologically assayed fluidextract is to be pre- 
ferred, but such preparations also become inert quickly, and therefore 
an effort should always be made to secure a fairly fresh preparation. — • 
Tr.] It is to be hoped that before long these preparations of incon- 
stant composition and uncertain strength will be superseded by the 
therapeutically valuable substances in pure and stable form. Until 
this is attained it is desirable that a satisfactory method of physio- 
logical assay should be devised and worked out thoroughly (Gottlieb). 

BIBLIOGRAPHY 

1 Barger and Dale: Journ. of Physiol., 1909, vol. 38. 

- Barger and Dale: Transact. Chem. Soc, 1909, vol. 95. 
3 Barger and Dale: Journ. of Physiol., 1910, vol. 40. 

Barger and Dale: Arch. d. Pharmazie, 1906, vol. 244. 
1 Barger, Carr and Dale: Chem. News, 1906, vol. 94, p. 89. 

- Barger, Carr and Dale: Journ. Chem. Soc, 1907, vol. 91, p. 337. 
3 Barger, Carr and Dale: Biochem. Journ., 1907, vol. 2, p. 240. 



HYDRASTIS AND COTARNINE 229 

Bennecke: Arch. f. Gvn., 1908, vol. S3, p. 669. 

Buehhehn: Arch. f. Pharm., 1875, vol. 2. 

Cronyn and Henderson: Journ. of Pharm. and exp. Ther., 1909, vol. 1, p. 203. 

Dale: Journ. of PhvsioL, 1906, vol. 34, p. 163. 

Gottlieb: Miinchn. med. Woch., 1908, p. 1265. 

Jacobi: Arch. f. exp. Path. u. Pharm., 1897, vol. 84. 

Kehrer: Arch. f. exp. Path. u. Pharm., 1908, vol. 58. 

1 Robert: Historische Studien a. d. Pharm. Inst, zu Dorpat, 1891. 

2 Robert: Realencyclopiidie d. gesamt. Pharrnazie, 1889, Mutterkorn. 

3 Robert: Arch. f. exp. Path. u. Pharm., 1884, vol. 18, p. 316. 

Robert u. Grunfeld: Arb. d. Pharm. Inst, zu Dorpat, 1892, vol. 8, p. 109. 

Rraft: Arch. f. Pharm., 1906, vol. 244, p. 336. 

Rielander: Marburger Sitzungsber., 1908, p. 173. 

Schmiedeberg : Grundriss d. Pharmakol., 5th Ed., p. 296. 

Vahlen: Arch. f. exp. Path. u. Pharm., 1906, vol. 55. 

Vahlen: Arch. f. exp. Path. u. Pharm., 1909, vol. 60. 

Wood and Hoier: Arch, of Int. Med., 1910, vol. 6, p. 388. 

Preparations of Hydrastis and of cotarnine are also employed in 
uterine hemorrhage. Hydrastine, from Hydrastis canadensis, and its 
derivative hydrastinine, also possess a peripheral exciting action on the 
uterus (E. Kehrer). Both alkaloids, but more especially hydrastinine, 
cause a general vasoconstriction and a rise of the blood-pressure, due 
both to a stimulation of the vasomotor centres and to a peripheral 
vasoconstricting action (Falk, Marfori). An entirely similar effect 
on the uterus is produced by cotarnine, which is a methyloxyhydras- 
tinine prepared from narcotine, an inactive opium alkaloid (Freund). 
This drug, like the others, also acts on the uterus directly. Its hydro- 
chloride and its phthalate are obtainable under the trade names of 
stypticin and styptol, and are employed in the treatment of uterine 
hemorrhage and also as uterine sedatives in disturbances of the men- 
strual function. 

Quite recently epinephrin has been employed for its effects on the 
uterus (Xcu). Its energetic oxytocic action has already been men- 
tioned. On account of the readiness with which it undergoes change 
in the organism, neither its intrauterine nor hypodermic administra- 
tion causes much rise of blood-pressure, but the small amounts which 
remain unchanged are sufficient, even after hypodermic administra- 
tion, to excite or to strengthen the contractions of the very readily 
excited muscle-fibres of the gravid uterus. It may, therefore, be used 
subcutaneously for the induction of labor, to strengthen labor pains, 
or to check uterine hemorrhage. 

After the birth of the child the use of this drug is free from 
danger, but clinical experience must decide whether, with careful 
dosage, its use during labor is unattended with risk of causing tonic 
(•nut ruction of the uterus with its peril to the child. 

This drug has also been directly injected into the uterine muscle 
to check post-partum hemorrhage, and also during cassarian section, 
both to render ili<' uterus bloodless for a time, and to secure its 
m;ixim;il rontracl ion. 






230 PHARMACOLOGY OF REPRODUCTIVE ORGANS 

According to still more recent observations, extracts of the infun- 
dibular portion of the hypophysis act like "a mild and under all 
conditions harmless epinephrin, " which, may be used in the same 
indications (Foges and Hofstdttcr, Hofbauer, Neu). 

BIBLIOGRAPHY 

Falk: Therap. Monatsh., 1896, p. 28. 

Foges u. Hofstatter: Zentralbl. f. Gyn., 1910, No. 46. 

Freund: Therap. Monatsh., 1904, p. 413. 

Hofbauer: Zentralbl. f. Gyn.. 1911, No. 4. 

Kehrer, E.: Monatssehr. f. Geb. u. Gyn., 1907, vol. 26, p. 709. 

Marfori: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 161. 

Neu: Gynakolopisehe Rundschau, 1907, p. 507. 

Neu: Die Bedeut. d. Suprarenins f. d. Geburtshilfe, Berlin, 1908. 

Neu: Miinchn. naed. Woch., 1911, No. 11, 



CHAPTER VIII 

PHARMACOLOGY OF THE CIRCULATION 

FACTORS CONTROLLING THE CIRCULATION 
Blood flow and blood-pressure are governed by three factors, — the 
quantity and quality (viscosity) of the blood, the work done by the 
heart, and the calibre of the vessels and their activity. The rapidity 
of the flow through the whole circulation depends on the reciprocal 
relationship of these factors. Directing our attention to the separate 
vascular sj'stems, we may for the time being consider the work done 
by the heart and the volume of the blood as constant, while the third 
factor — that is, the state of contraction of the vessels — changes from 
moment to moment according to the needs of the various organs. 

In general it may be said that, under physiological conditions, the 
more active an organ is the more blood will it contain, for, as every- 
where in the body, the rule, that a physiological activity brings about 
conditions which favor its efficient accomplishment, holds good for the 
relationship between the activity of an organ and its blood supply: 
The demand creates a supply, so that the activity of an organ governs 
its blood supply. 

This vasodilatation of active organs is brought about by reflexes causing 
inhibition of vasoconstriction as well as stimulation of vasodilators, and sub- 
stances formed during the activity of the organ act locally on the vessel walls, 
causing local vasodilatation {Gaskell, Loeioi u. Henderson). 

The activity, or inactivity, of the various organs may bring about 
very marked changes in the distribution of the blood. The muscles of 
a rabbit at rest contain but 33.6 per cent, of the total blood, but 
this percentage is increased to 66 per cent, or more during violent 
muscular effort (Ranke u. Spehl) . With the dilatation of so many 
vessels resulting from general muscular activity and the resultant 
decrease of the resistance, there would necessarily be a very marked 
fall in the general blood-pressure, and a slackening of the blood flow 
in nt her organs (e.g., in the heart and central nervous system), were 
there not an efficient compensating mechanism to prevent this. The 
conditions which prevail during muscular activity show that there 
is ample provision for such compensation, for, as a matter of fact, 
blood-pressure actually rises during muscular activity (Zunl: u. 
Tangl, Tiedemann, Krone). This compensation is brought about 
not only by an increased efficiency of the heart function, but also 
by a narrowing of the vessels in other organs, — e.g., the portal vessels, 
which compensates foe the dilatation of the vessels in the muscles. 
On the other hand, although during digestion the abdominal viscera 
are more richly supplied with blond, the other organs receive <-om- 

231 



232 PHARMACOLOGY OF CIRCULATION 

paratively little, so that the aortic pressure is not necessarily lowered 
(Pauiow). 

There is thus a continuous compensatory balance maintained be- 
tween the different vascular systems, especially between the portal 
system and the peripheral vessels in the skin, muscles, and brain. This 
reciprocation between these two great systems is well illustrated when 
the depressor nerve is stimulated, there resulting a dilatation of the 
visceral vessels and a contraction of the peripheral ones (Bayliss, 
Dastre <t Moral). On the other hand, stimulation of sensory nerves 
or of the splanchnics, or asphyxia, causes a vasoconstriction of the 
abdominal vessels and dilatation of most of the vessels of the skin, 
muscles, and brain. We find this same difference in behavior resulting 
from the administration of various drugs (epinephrin, digitalis, strych- 
nine, and others) . Other combinations are also possible, — for example, 
cold applied to the skin causes contraction of the cutaneous and renal 
vessels, while the other visceral vessels dilate (Wertheimer, 0. Mutter)'. 
Mental activity causes an increased blood supply to the brain and a 
lessened supply to the skin and muscles of the head and to the 
abdominal viscera {Mosso, Weber). 

This regulation of the distribution of the blood is, in part, reflex in its 
mechanism. For instance, when the internal vessels are constricted, the vaso- 
dilatation in the extremities is partly the result of central nervous action 
[Deh zenne), but it also results in part from a forcing out of the blood from the 
constricted vascular systems into others, the vessels of which are thus mechani- 
cally dilated. In certain vascular systems which are little, if at all, under vaso- 
motor control, the changes in the blood supply are brought about entirely in 
the latter fashion. 

Although we have but a limited knowledge of the details of the 
various compensatory regulations by which the different vascular sys- 
tems maintain the equilibrium of the circulation, we know that dis- 
turbances of this compensatory mechanism play an important role in 
pathology. We know too that in the circulatory action of drugs the 
decisive factor is often the changed distribution of the blood and 
not the change in the aortic pressure. If, for any reason, in con- 
ditions in which the blood distribution is altered from the normal, this 
compensatory regulation does not occur, its mechanical results affect 
the whole circulation, including the heart itself. 

This occurs when important and extensive vascular systems are 
relaxed and when compensation therefor does not occur. In such case 
the total amount of blood in the body is not sufficient to fill the relaxed 
vessels, for the total volume of blood is sufficient for the filling of the 
vascular systems only when the total cross-section of the vascular tree 
is equal to its normal mean, which mean is ordinarily maintained 
by the changing play of the vasomotor mechanism. Therefore, in 
conditions of vascular paresis, it is evident that the heart is unable 
to work efficiently, for, when the vascular system has lost its tone, the 
left heart pumps its blood not into an elastic system of tubes which 



FACTORS CONTROLLING CIRCULATION 233 

are able to deliver their contents back to the right heart, but it pours 
it out into a relaxed system in which the blood must stagnate to a 
greater or less extent. As a result the heart is insufficiently supplied 
with blood. 

As shown above, uncompensated vasodilatation impairs the heart 
action, and the same is true when wide-spread vasoconstriction occurs. 
In the latter case, as a result of the increased peripheral resistance, the 
blood-pressure must rise greatly, and, if compensatory relaxation of 
other vessels does not occur to relieve the heart, the left ventricle may 
no longer be able to empty itself against the excessive pressure, and 
stasis of the blood in the heart results (Tigerstedt). 

This short discussion has already shown how the activity and 
efficiency of the heart depend on the maintenance of a mean total 
cross-section of the vascular tree by the interplay of the different 
vascular systems (Hensen). Clinically, this is clearly evident, for, 
under different conditions of increased or diminished cardiac activity 
(tachycardia, fever, disturbance of compensation, etc.), causing marked 
variations in the blood flow, there may be no change in the radial 
blood-pressure, the vascular system by compensatory dilatation or 
contraction accommodating itself to the varying output of the heart. 
Ever since the observations of Tappciner and Worm-Miiller, it has 
been known that the blood-pressure quickly regains its former height 
even after extensive loss of blood, and it is under just these conditions 
that we may especially well observe this accommodation of the vascular 
system to varying states of fulness. Although after hemorrhage an 
inpouring of fluid from the lymph and tissues plays an important part 
in restoring the blood-pressure, its rapid re-establishment is chiefly 
due to the fact that the vessels throughout the body contract about 
their diminished blood contents. On the other hand, in artificial 
plethora the blood-pressure is raised only by very great overfilling 
of the vascular system, and even then but momentarily (Cohnlu im) . 

The circulation is further protected from disturbance by another 
adaptive mechanism, which helps to maintain the proper equilibrium 
between the arterial and venous systems. If the blood is to be kept 
circulating normally, it is essential that during a given period the same 
quantity of blood must pass each total cross-section of the vascular 
tree, — that is. in a given period as much blood must enter the heart 
from the veins as leaves it to enter the arteries. If this balance be 
(list iii-bed, the blood will accumulate in some portion of the circu- 
latory system, most likely either in the heart itself or at the point 
where the arterioles and capillaries join with the veins. Epinephrin 
injections, by increasing the resistance in the arterioles, may cause an 
overfilling of the arterial portion, or a dilatation of the capillaries 
may cause ;m accumulation at this point with a resulting "capillary 
stasis." while insufficient cardiac* activity may lead to an accumulation 



234 PHARMACOLOGY OF CIRCULATION 

of blood in the heart itself, in the pulmonary system, and in the 
great veins emptying into the heart, — " cardiac stasis." 

Everywhere we see that disturbances of the heart function produce 
effects on the vascular system and that the changes in the vessels 
affect the cardiac function. With such reciprocal action of the 
separate factors and such mutual interdependence, it is evident that 
there can be no such thing as a pharmacological action affecting exclu- 
sively either the heart or the vessels, for, just as pathological altera- 
tions of the heart or vessels necessarily affect the whole circulation, so 
it is with those produced by pharmacological agents. Bearing these 
facts in mind, it is evident that, in the analysis of pharmacological 
actions of the various circulatory drugs, it is essential to determine 
their primary seat of action, as this often renders it possible to explain 
the whole combination of the phenomena resulting from their adminis- 
tration. Therefore the action of drugs on the heart and on the vessels 
will be discussed separately, while their effects on the circulation as a 
whole will be taken up later. Moreover, in any investigation of such 
drugs one should first of all endeavor to determine whether a drug acts 
primarily on the heart or on the vessels. 

BIBLIOGRAPHY 

Bayliss: Journ. of Physiol., 1893, vol. 14, p. 303. 

Cohnheim: Yorles. u. allgem. Pathologic, 18§2, vol. 1. 2d ed., p. 400. 

Dastre et Morat: Systeme nerveux vasomoteur, Paris, 1884, p. 330. 

Delezenne: Journ. of Physiol., 23, Suppl., 1898-1899, p. 4. 

Gaskell: Journ. of Physiol., 1880-1882, vol. 3, p. 48. 

Henderson u. Loewi: Arch. f. exp. Path. u. Pharm., vol. 53, p. 62. 

Hensen: Deut. Arch. f. klin. Med., 1900, vol. 47. 

Krone: Miinehn. med. Woch., 1908, No. 2. 

Mosso: Arch. ital. de Biol., 1884, vol. 5. 

Miiller: Deut. Arch. f. klin. Med., 1905, vol. 82, p. 574. 

Pawlow: Pflliger's Arch., 1879, vol. 20, p. 210. 

Ranke u. Spehl: cited from Tigerstedt, Physiol, d. Kreislaufes, 1893, p. 551. 

Tiedemann: Deut. Arch. f. klin. Med., vol. 91, p. 331. 

Tigerstedt: Skand. Arch. f. Physiol., 1907, vols. 19 and 20. 

Weber: Engelmann's Arch., 1907, p. 293, and 1908, p. 189. 

Wertheimer: Arch, de Physiol., 1894, p. 308. 

Worm-Miiller: Ludwig's Arbeiten aus d. Physiol. Anstalt in Leipzig, 1872 and 

1873. 
Zuntz u. Tangl: Pfliiger's Arch., 1898, vol. 70, p. 544. 

METHODS OF INVESTIGATING THE CIRCULATION 

The experimental pharmacology of the circulation started with the 
study of the changes in the aortic blood-pressure resulting from the 
administration of various drugs and poisons. The mean pressure 
in the aorta must furnish enough hydrostatic pressure to maintain 
a flow of blood through the various organs which will be sufficient 
properly to maintain their various functions. A decided fall in 
aortic pressure is, therefore, in itself a sign of marked disturbance 
throughout the circulation. As, however, the aortic pressure represents 
only a gross value resulting from the momentary efficiency of the 



METHODS OF INVESTIGATION 



235 



heart and the total vascular resistance, other supplementary methods 
are needed for the determination of the separate factors. 

Before starting on a close analysis of the blood-pressure as studied 
in animal experimentation, it is proper to discuss briefly the methods 
used in the clinical observations of the circulation in man, for the 
more refined actions of drugs often stand out more sharply under 
pathological than under normal conditions. 

CLINICAL METHODS 

Sphygmograms. — Some deductions may be made as to the func- 
tional activity of the heart and the condition of the vessels from the 
graphic registration of the radial pulse. The form of the pulse wave — 
i.e., the course of the pressure changes in the radial — is dependent 
on the one hand, on the work done by the heart and, on the other, 
on the resistance in the vascular system (0. Frank). The sphygmo- 







Normal pulse. 



Dicrotic pulse — low peripheral resistance. 




Tense pulse — high peripheral resistance (case of lead colic). 



gram is altered from the normal by various pathological conditions, 
as, for example, in aortic insufficiency, by the fact that the blood 
leaves the arteries in both directions or that in arteriosclerosis it 
flows out but slowly from the inelastic vessels (Sahli). In a similar 
manner pharmacological agents may influence the form of the pulse- 
wave, should they change either the inflow into the aorta — i.e., the 
"pulse volume" of the heart — or alter the rate of outflow into the 
capillaries by affecting the calibre of the vessels. With due allowance 
for technical difficulties, it may be stated, with reasonable certainty, 
thai When the peripheral resistance is low the dicrotic wave will be 
well developed in the sphygmogram while the so-called "elasticity" 
elevations tend to disappear, while with increased peripheral resist- 
ance the opposite occurs (Fig. 17a). In spite of all uncertainty in 
the interpretation of sphygmographic curves, the position of the 
anacrotic wave high up on the ascending curve near its summit, a 
rounded summit or a plateau-like one, indicates hitdi tension in the 
arteries. 



236 PHARMACOLOGY OF CIRCULATION 

Changes in the pulse tracings are frequently evident after the 
administration of drugs and poisons which influence the vessel calibre. 
Thus, during the attacks of spasmodic contraction of intestinal vessels 
which occur in lead colic, the pulse is that of high tension, with diminu- 
tion or disappearance of the dicrotic wave and the presence of an 
anacrotic elevation. On the other hand, vasodilating drugs, such as 
chloral (in large doses), cause the pulse to resemble that of fever. 
During the treatment of vascular spasms by amyl nitrite, one may 
often observe the transition of the pulse from one form to another 
(Fig. 17b). In such case the change in the sphygmogram is much 
less the result of the vasomotor changes in the radial artery and its 
branches than of the alteration of the general vasomotor tone, which 
is the decisive factor for the whole circulation (Sahli). 

The clinical determination of the blood-pressure is of much 
greater significance for the pathology and pharmacology of the circu- 
lation. The technic of blood-pressure determination has in recent time 
reached such perfection that the maximal systolic pressure may be 




(6) 



Fig. 17b. — Sphygmograms from case of lead colic: o, before, b, after inhalation of amyl nitrite. 

determined with a high degree of accuracy, while the diastolic mini- 
mum may be approximately estimated.* From these two values one 
may determine the variation in pressure in the radial arteries (pulse- 
pressure) and its relation to the mean pressure. "While the older 
methods of v. Basch, Riva-Rocci, Gartner, and others gave clinically 
valuable but only approximately correct values, v. Recklinghausen's 
modification of Riva-Rocci 's method has a percentage of error of but 
7 to 9 per cent, for the maximal pressure, as has been shown by the 
direct measurement of the brachial pressure in an arm just prior 
to amputation. The determination of the minimal diastolic pressure 
is more difficult, and up to the present time is attended by greater 
factors of error. [See footnote. — Tr.] 

The most important results obtained by clinical observations of 
blood-pressure have been the demonstration that a marked rise in 
blood-pressure often occurs in disease, but that, contrary to our for- 
mer views, a marked fall in blood-pressure actually occurs much less 
frequently, and is observed, as a rule, only a short time before com- 

* [By the ausculatory method both may be determined with quite sufficient 
accuracy. — Tr.] 



METHODS OF INVESTIGATION 237 

plete failure of the circulation. Even in cardiac decompensation, 
marked lowering' of the blood-pressure is the exception, for the 
pressure is maintained near the normal level by compensatory vaso- 
constriction, and thus the best circulation possible is maintained in 
the vital organs. This regulation by the vessels so complicates blood- 
pressure conditions that the essential question, whether the primary 
seat of a pharmacological action be in the heart, vessels, or nervous 
system, can never be answered without further information than that 
obtained by the methods discussed above. 

BIBLIOGRAPHY 

Prank, 0.: Ztschr. f. Biol., 1905, vol. 46, p. 441. 

Miiller, Otfried: lied. Klin., 1908, Nos. 2-4. 

v. Recklinghausen: Arch. f. exp. Path. u. Pharm., 1906, vol. 55, p. 376. 

Sahli: Klinische Untersuchungsmethoden, 5th edition, 1908, p. 19. 

EXPERIMENTAL METHODS 

Only by closer analysis of the blood-pressure in experiments on 
animals can such information be obtained. Here methods may be 
used which are beyond criticism and which enable us to determine 
the causes of rise or fall in blood-pressure, at any rate for those 
grosser changes which are not compensated for by the regulatory 
mechanism. 

A fall in the aoetic pressure may be due to the lessened inflow 
of blood resulting from a diminished output by the heart, or it may 
result from a lessening of the resistance in the vessels. If a fall in 
pressure is caused by a general vasodilatation, then the blood-pressure 
will be re-established at its normal level if the total vascular cross- 
section be artificially diminished. This may be accomplished by clamp- 
ing the aorta, which will cause the blood-pressure to return to its 
normal level if lessened resistance were the cause of the fall. 

It having in this fashion been shown that the fall of blood-pressure 
was due to vasodilatation, it must further be determined if the loss 
of vessel tone is due to an interference with the central or the 
peripheral vasoconstrictor mechanism. Electric stimulation of the 
vasomotor centre in the cervical cord or of the vasomotor nerves — e.g., 
the splanchnies — may then be employed to test the excitability of the 
peripheral mechanism. 

In case a drug has caused a rise of blood-pressure as a result 
of a wide-spread vasoconstriction, it must similarly be determined 
whether this be due to stimulation of central or of the peripheral 
vasoconstrictor mechanisms. To decide this, the cervical cord may 
be cut and the effect on blood-pressure noted. To exclude action of 
the secondary vasomotor centres in the cord, this too may be de- 
stroyer! by pithing. Centrally acting drugs, such as strychnine, will 
under these conditions no longer raise the blood-pressure. If, however, 
the drug still affects the blood-pressure in the aorta, it must act 



238 PHARMACOLOGY OF CIRCULATION 

peripherally — that is, in the vessel walls themselves. Substances of 
the digitalis group, epinephrin, and barium salts are examples of drugs 
which under the above conditions may still cause a marked rise of 
blood-pressure. 

If the relaxation of the vessels is caused by depression of the 
vasomotor centres, the diminution in their excitability may be fol- 
lowed step by step if different stimulating agents be used. These 
centres first lose their reflexive excitability to stimulation through the 
sensory nerves, the blood-pressure failing to rise after stimulation of 
the sciatic. Chemical stimuli are the next to lose their effect, and 
therefore the blood of asphyxia, normally a vasoconstrictor stimulant, 
may be used as a means of testing their excitability. Finally, in com- 
plete paralysis of the vasomotor centres, even direct electric stimulation 
of the cervical cord is without effect. 

If the vascular paresis be peripheral, it is self-evident not only that 
the above-mentioned stimulants of the vasomotor centres will produce 
no effect, but also that stimulation of vasomotor nerves will be ineffec- 
tual. If, for example, one is dealing with a peripherally induced 
paresis of the portal vessels, such as occurs in arsenic poisoning, the 
stimulation of the splanchnics will, as the poisoning develops, produce 
constantly diminishing effects. 

Through such experiments it is possible to determine definitely 
whether or not the action in question is dependent or not on the central 
nervous system. We cannot, however, by these methods determine 
at all whether the changes in the blood-pressure result exclusively from 
peripherally caused changes in the calibre of the vessels, or whether 
they also in part arise from changes in the cardiac function. This may 
be decided beyond question only by a further analysis, during which 
the action on the heart and that on the vessels may be better differ- 
entiated. 

Repeatedly attempts have been made to exclude the central vasomotor inner- 
vation and the peripheral mechanism by the use of large doses of depressing drugs, 
such as chloral hydrate or amyl nitrite, and then to test the action of blood- 
pressure-raising (pressor) substances. However, this method of experimentation 
is not free from sources of error, for the second drug may overcome the vascular 
paralysis and thus the deduction of a pure cardiac action be unjustified. 

METHODS FOR STUDYING THE EFFECT OF DRUGS ON THE 
CARDIAC FUNCTION 

If an effect on blood-pressure is not the result of changes in the 
calibre of the vessels, it has usually been concluded that it is due to a 
change in the work performed by the heart, and the endeavor has 
been made to supplement the analysis of the blood-pressure by ex- 
perimentation on the isolated surviving heart. In addition, by the 
simultaneous graphic registration of the blood-pressure and of the 
functional activity of the heart by plethysmography of this organ 
or by similar methods, further data for the estimation of the activity 



METHODS OF INVESTIGATION 



239 



of the heart may be obtained. However, the real decisive factor, the 
pulse volume of the heart, may be exactly determined in the intact 
circulation only by measuring the amount of blood which the heart 
pumps out into the aorta. The measurement of the volume per 
minute, by the use of a Tigerstedt's " Stromuhr " placed in the aorta, 
has recently given results of much importance in connection with the 
study of the action of epinephrin, the digitalis group, etc. 

BIBLIOGRAPHY 

Knoll: Bericht d. Wien. Akad. d. Wiss., 1S80, vol. 82. 

Lehndorff : Arch. f. exp. Path. u. Pharm., 1909. vol. 61, p. 418. 

Pvoy and Adams : Philosoph. Transact, vol 183 p. 302. 

Tigerstedt: Skandinav. Arch, f Physiol. 1891, vol. 3, and 1907, vol. 19. 

Observations on the isolated frog's heart have rendered to pharma- 
cology invaluable service in the determination of the seat of action of 
drugs affecting the circulation, the classical material for such observa- 
tions being the surviving frog's heart. 



/VWvv— 1- 




Fig. 18. — Williams's frog-heart apparatus. 

In lsiiii Cyon, in C. Ludwig's laboratory, was the first to conduct such 
experiments. Soon after this W. Blasius and Buhm used the same method in 
Pick's laboratory. At first the frog's heart was used with the sinus, auricles, 
and valves attached, the heart receiving the artificial nutrient solution (diluted 
blood, rabbit serum, or Ringer's solution) through one vena cava and expelling 
it through the aorta, the other veins and arteries having been ligated. The 
observation of the surviving frog's ventricle was further simplified by the use 
of Kronecker'a frog-heart manometer, in the use of which a double cannula was 
introduced into the ventricle after removal of both sinus and auricle. Straub'a 
simple method is for many purposes the best. In it the heart receives the 
nutrient solution through a simple funnel cannula from a column of fluid of a 
minimal height of 2-3 cm. By its own beats it. keeps the fluid well mixed and 
may continue actively beating for hours. 

Fdi- tlic pharmacologist William's frog-heart apparatus ( Fig. 18) 
is the most, useful. By means of artificial valves, which take the place 



240 PHARMACOLOGY OF CIRCULATION 

of the cardiac valves, the nutrient solution circulates in this apparatus 
through a rigid system of tubes under pressure conditions which may 
be altered at will. 

Two glass reservoirs of about 30 c.c. capacity are used as containers for 
the normal solution and for the solution containing the drug. The rubber tubes 
from these are joined together by a Y-tube, through which either solution may be 
conducted through the valve of ingress to a double cannula which leads into the 
ventricle. The other branch of this cannula is connected with a second valve, 
which, like the aortic valve, keeps the solution from flowing back into the ven- 
tricle but permits it to return to the reservoir. A manometer is connected to 
that part of the system which represents the arterial system. By narrowing 
or widening the point of exit from this system, the pressure may be varied at 
will in this tube which represents the aorta. 

As soon as the necessary resistance is produced, each heart-beat causes a 
certain rise in pressure in the manometer. If this resistance to the outflow be 
kept constant, a change of the mean pressure or in the size of the pulse in the 
fixed system of tubes can be the result only of a change in the functional activity 
of the heart. With this apparatus the pulse volume of the heart may be deter- 
mined either by measurement of the fluid pumped out or by plethysmographically 
recording the changes in volume between the systolic and diastolic phases of the 
ventricle. The work done by the heart may at any time be calculated either 
for the unit of time or for the individual heart-beat, for the work done is the 
product of the amount pumped out, the pulse volume, multiplied by the pressure 
against which the heart empties itself. If this pressure be increased by raising 
the outflow point, a pressure may be reached which the heart is no longer able 
to overcome. Thus the absolute power or strength of the heart is determined 
(Dreser) . 

BIBLIOGRAPHY 

Blasius: Yerhandl. d. Physikal.-med. Ges. zu Wiirzburg, 1871, vol. 2, p. 49. 

Blasius: Pfliiger's Arch., 1872, vol. 5, p. 153. 

Cyon: Ber. d. Kgl. Sachs. Ges. d. Wiss., 1866, p. 256. 

Dreser: Arch. f. exp. Path. u. Pharm., 1887, vol. 24, p. 227. 

Kronccker, H. : Beitr. zur Physiol., Leipzig, 1874, p. 173. 

Straub: Biochem. Ztschr., 1910, vol. 28, p. 392. 

Williams: Arch. f. exp. Path. u. Pharm., 1880, vol. 13, p. 1. 

Experiments on the Isolated Mammalian Heart. — By perfusing 
its coronary vessels the isolated mammalian heart may also be kept 
beating for hours. By this method, too, or by the method of Hering 
and Bock (see below), it is possible to study the action of drugs on the 
heart while excluding any actions on the general vascular system. 

The method of Hering and Bock (Fig. 19) is as follows: 

The descending aorta and both subclavians of a rabbit are ligated. One 
carotid having been connected with a manometer, from the other the blood passes 
through a U-tube into the jugular vein. The pulmonary vessels are left undis- 
turbed, and the blood passing through the lungs is arterialized and enters the 
left heart. It then passes through the aorta into the carotid, through the glass 
tube into the jugular, through which it then flows back into the right heart. The 
glass tube thus replaces the general vascular system, but in it the resistance 
remains constant. The pulmonary circulation is not disturbed, but this may be 
disregarded, for the pulmonary vessels are little or not at all affected even by 
the most powerful vasoconstricting or vasodilating drugs (Gerhardt). The 
vascular system under these conditions is thus represented by a system of tubes, 
which with the exception of the coronary vessels must maintain a constant 
resistance. 



METHODS OF INVESTIGATION 



Ml 



The heart is physiologically isolated, so that any change in blood- 
pressure in this system must be the result of an alteration in the 
cardiac function. 

The method of perfusion of the surviving mammalian heart, chiefly 
developed by Langendorff , depends on a fact already observed by 
Ludwig, who found that even an isolated mammalian heart may survive 
and continue to beat if the coronary vessels be perfused at body tem- 
perature with defibrinated blood or other appropriate nutrient solu- 
tions. Under such conditions a heart may continue to beat for hours 
if kept in a moist chamber and under proper conditions. 

Langendorff causes the blood to flow into the aorta under pressure, and, 
as the aortic valve remains closed, the only outlet for the blood is through the 
coronary vessels, from which it flows into the right auricle, leaving the heart 
here. The cavities of the heart remain empty, but the heart beats for long 
periods with satisfactory regularity if the supply to the coronary vessels is suffi- 



Vena jugular 



Right heart • • • 




■ ••Left heart 



\^m 



cient and constant and if the temperature be maintained constantly at the right 
degree. If these conditions be maintained, any changes in the action of the 
heart may be attributed to the drug which is perfused. A heart perfused accord- 
ing to this method preserves a fairly normal excitability of both its muscular 
ami nervous elements, so that it will respond to both vagus and accelerator 
stimulation (Langendorff, llering, Steinberg) . 

BIBLIOGRAPHY 

Bock: Anli. f. exp. Path. u. Pharm., 1808, vol. 41. 
Gerhardt: Arch. f. exp. Path. u. Pharm., 1!)00, vol. 44. 
Hering, II. E.: Pflttger's Arch., 1898, vol. 72, p. 163. 
Il.-iin-. II. !•:.: Plliiger's Arch., 1003, vol. 99, p. 245. 
Langendorff: Pfluger's Arch., 1895. vol. 01, p. 291. 
Steinberg: Ztachr. f. Biol., 1008, vol. 51. 
Hild: Ztschr. f. rat. Med., 1840, vol. 5. 



METHODS FOR STUDYING PHARMACOLOGICAL ACTIONS 
ON THE VESSELS 

The pharmacological investigation of surviving vessels is also 
feasible, for the vessels of organs removed from the body and properly 
perfused with appropriate solutions at body temperature also "sur- 

16 



242 PHARMACOLOGY OF CIRCULATION 

vive" for a considerable period. If the perfused fluid be allowed to 
flow under constant pressure through the arteries of such organs as 
the kidney, spleen, or an extremity, and the amount flowing out in a 
unit of time be noted, any increase or diminution in the rate of flow 
can be due only to a change in the calibre of the vessels, the cause of 
which must lie in the vessel walls themselves. 

Mosso, in Ludwig's laboratory, making use of the method of perfusion, 
was the first to demonstrate the peripheral action of a drug on the vessel walls. 
It must, however, not be forgotten that surviving vessels are no longer under 
physiological conditions, even when perfused with defibrinated blood, which is so 
especially suitable for the maintenance of the chemical processes in the tissues, 
for the blood never flows through a surviving organ so rapidly as it would in the 
living animal under like conditions of pressure and inflow, and its rate of 
outflow diminishes progressively with the lapse of time. Moreover, even slight 
variation in the composition of the artificial nutrient solution from that of normal 
blood — for example, the defibrinization — is of moment here. The method is thus 
necessarily one attended by many sources of error. Perfusion with blood-free 
Ringer's solution gives the most constant results. 

Recently a new experimental method has been devised which per- 
mits of the direct observation of changes in the tone of excised circular 
strips of the arteries. By proper treatment in Ringer 's solution main- 
tained at body temperature, isolated vessels may be maintained for 
days in an excitable condition, so that drugs acting peripherally will 
exert their specific action on such material (v. Frey, J. B. Meyer, 
Langendorff). 

The peripheral actions on the vessels are, however, in no way alone 
responsible for the behavior of the different vascular systems in the 
living body, where they are under the influence of the central nervous 
system and, as previously stated, are often influenced by various com- 
pensatory regulations. Other methods (F. Pick, Biedl, Barcroft and 
Brodie) are, therefore, needed which will permit the determination 
intra vitam of the blood flow through the different organs, in order 
that we may determine the role played by the various vascular systems 
in the circulatory changes taking place throughout the body. Here 
observations of the outflow from veins and plethysmography are of 
value. 

A plethysmogram shows the changes in volume taking place in an 
organ enclosed, with its afferent and efferent vessels, in an air-tight 
container constructed especially for this purpose. Boy, using his 
oncometer, was the first to measure the volume changes of the kidney, 
but at the present time Schaefer's plethysmographs are usually used. 
If the container is connected with an apparatus for registering 
changes of volume, such as the piston recorder, the separate pulse- 
waves are visible, the increase of volume of the organ caused by each 
heart-beat driving air out of the oncometer. In the same fashion the 
volume of the enclosed organ follows the changes in blood-pressure 
during longer periods, the vessel being passively dilated by increased 
blood-pressure or less completely filled as the pressure falls. 



METHODS OF INVESTIGATION 



243 



Thus, the plethysmography curve moves in the same direction as the 
blood-pressure curve if the vessels in the enclosed organ are not themselves 
influenced by the drug employed. If these vessels, however, are contracted, the 
volume of the organ does not increase, but, on the contrary, diminishes, as the 
blood-pressure rises, and the two curves move in opposite directions; while, on 
the other hand, if the enclosed vessels actively dilate, the plethysrnographie curve 
rises, although the blood-pressure remains constant or even if it falls, and thus 
this curve may cross the blood-pressure curve. In Fig. 20 is seen a plethysrno- 
graphie curve obtained from a loop of gut enclosed in a plethysmograph. This 
shows the changes in the volume of the intestines during stimulation of the 
splanchnic nerve. This method, as also the outflow method, permits of the simul- 
taneous determination of the blood flow through several organs and of their 
influence on each other. Pharmacological vasomotor actions may also be analyzed 
after section of the vasomotor nerves, and in such experiments electric stimula- 
tion of these nerves is often employed. 



Volume of intestine 




Stim. of splanchnic 



Fia. 20. — Effect on intestine of stimulation of the splanchnic (Lchndorff) . 



BIBLIOGRAPHY 

Barcroft and Brodie: Journ. of Physiol., 1005, vol. 32, p. 18. 

Biedl: Pflttger's Arch., 1897, vol. 67, p. 446. 

Brodie: Journ. of Physiol., 1903, vol. 29, p. 2GG. 

Frey: Sitz.-Ber. d. Phvsikal.-mcd. Gcs., Wttrzburg, 1905. 

Langendorff: Zentralbl. f. Physiol., L908, vol. 21, No. 17. 

Lehndorff, Arno: Engelmann's Arch., 1908, p. 3(i - 2. 

Meyer, J. B.: Ztschr. I. Biol., 1907, vol. 30, p. 352. 

.\l'i--,, : |'h\ inl. Anslalt zu Leipzig, 1874, p. 30.1. 

Plafl u. Vejnx-Theyrode: Arch. f. exp. Path. u. Pharm., 1903, vol. 49, p. 324. 

Pick, P.: Arch. f. exp. Path. u. Pharm., 1899, vol. 42, p. 399. 

Roy: Journ. of Physiol., 1881, vol. 3, p. 203. 

Bchafer and Moore: Journ. of Physiol., 1890, vol. 20, p. 5. 



244 PHARMACOLOGY OF CIRCULATION 

PHARMACOLOGY OF THE HEART 

All the factors necessary to its activity are contained within the 
heart itself. Normally the stimuli for the automatic cardiac move- 
ments in the frog's heart originate in the sinus venosus, and in the 
mammalian heart at the mouth of the great veins (Adam), the rhythm 
of the heart being normally determined at these points, — that is, 
the motor stimuli for the heart are here transformed into rhythmic 
stimuli ( Gashill and Engchnan n ) . The function of these motor centres 
in the heart may be variously influenced by drugs and poisons. 

A brief explanation of the frequently observed vital phenomenon known as 
rhythm (Steinach) may aid in our understanding of these points. One of the 
comparatively few established and fundamental properties of all nervous centres 
(either ganglia or nerve-plexuses) is their power to summate continually arriving 
stimuli and thus to make them effective. After a certain period this summation 
results in a discharge of energy from the nervous organ, which is succeeded by a 
phase of exhaustion, during which the centres remain refractory — that is, insus- 
ceptible to stimulation — until sufficient energy has again been developed in them, 
catabolic and anabolic processes thus alternating. This periodicity of function 
in the centres has as its visible effect the periodic activity of the organs under 
their control, — e.g., the respiratory muscles, the heart, etc. For such centres as 
are normally constantly called upon, this refractory phase is a vital necessity, 
enabling them to develop again the energy needed. 

The fundamental work of Gaskell and Engelmann has demon- 
strated that in the study of cardiac activity we must differentiate be- 
tween the different cardiac functions which are involved, as these 
may be separately affected by different pharmacological agents. The 
frequency with which stimuli pass to other portions of the heart is 
normally controlled by the state of the stimulus-producing mechanism 
in the sinus (chronotropic or retarding influence of the sinus). This 
mechanism determines the rhythmic activity of the heart, which is the 
first of its physiological characteristics to be considered. 

It may further be shown that such stimulus-inaugurating mechanisms exist 
not only at the situations mentioned but also in all parts of the heart. However, 
the automatism of the lower portions of the heart is only latent, — that is, it 
remains inactive as long as the controlling mechanism in the sinus is active 
and inhibits these secondary ones. This is analogous to the phenomena of intra- 
central inhibition in the central nervous system. 

The functional activity of the ventricles is controlled and may be 
pharmacologically influenced by the following factors: 

1. The power of rhythmical activity of the stimulus-producing 
mechanism in the sinus, — chronotropic function. 

2. The rate of conduction of stimidi in the heart, — dromotropic 
function. 

3. The functional capacity of the excitable peripheral motor 
mechanism in the heart (nerves or muscles), — bathmotropic function. 

4. The momentary internal condition of the heart muscle, which 
alone, quite independently of the strength of the stimulus, determines 
the extent and power of the contraction, — inotropic function. 



PHARMACOLOGY OF THE CARDIAC NERVES 245 

All these different functional attributes of the heart are sus- 
ceptible of influence through both the extracardial and the intracardiac 
nerves, the heart receiving from the central nervous system a double 
nerve supply, the inhibitory vagus from the cranial autonomic para- 
sympathetic system and the accelerator fibres from the sympathetic 
system. Both nerves may be acted upon by drugs at their points of 
origin in the central nervous system as well as peripherally in the 
heart. 

BIBLIOGRAPHY 

Adam: Pfliiger's Arch., 1906, vol. Ill, p. 007. 

Steinach: Pfluger's Arch., 1908, vol. 125, pp. 239 and 290. 

PHARMACOLOGICAL ACTIONS ON THE EXTRACARDIAL NERVES 

The inhibitory centre in the medulla is directly stimulated 
by a number of agents, the best-known example of this being its 
stimulation by the blood of asphyxia. Certain medullary convulsants 
(Krampfgifte) , such as picrotoxin and cicutoxin, like asphyxia, simul- 
taneously stimulate the vagus and the vasomotor centres (Bohm). 
Epinephrin (Verworn, Biedl u. Reiner) and the digitalis group 
( Koch ma nn) also directly stimulate the vagus centre independently 
of their indirect actions on it. However, in the case of those sub- 
stances which cause a rise in blood-pressure, as also in asphyxia, it is 
extremely difficult to distinguish between a direct stimulation of the 
vagus centre and an indirect stimulation resulting from the rise in 
blood-pressure. 

As shown by Bernstein, the tone of the vagus centre depends on the 
height of the blood-pressure, it being augmented by a rise in blood- 
pressure, such as that caused by a temporary overfilling of the arterial 
system, while during a fall in blood-pressure, such as follows hemor- 
rhage, the pulse becomes more rapid, the vagus centre being rendered 
less susceptible to reflex influences. It therefore follows that the rate 
of the heart is altered secondarily by all pharmacological agents which 
raise or lower the general blood-pressure. Thus, the pulse is slowed 
by the rise in blood-pressure produced by strychnine and accele- 
rated by the fall caused by amyl nitrite, although these drugs have 
no direct action on the vagus centre. 

As is well known, section of the vagi is followed by more or less 
pronounced acceleration of the pulse, this being due to the abolition 
of the rostra in ing influence of this centre, and varying in intensity 
according to the species of animal in question. It is self-evident that 
after si i! ion of the vagi there can be no slowing of the pulse through 
any stimulation of this centre by drugs or other agents. Paralysis 
of the vagus centre by drugs or poisons produces the same results as 
Bection of the nerves, and causes a corresponding acceleration of the 
pulse, which varies in extent with the animal observed. 

Acceleration of the pulse may also be due to stimulation of the 
accelerator centn s. 



246 PHARMACOLOGY OF CIRCULATION 

The acceleration of the pulse preceding vomiting is an example of the 
effect of such accelerator-centre stimulation. Further, the blood of asphyxia 
stimulates this centre just as it does the vagus centre. Therefore, asphyxia 
of a curarized animal causes acceleration of the pulse if the vagus has been 
eliminated by section or otherwise (Dost re et Morat, Konow u. Stenbeck). So 
long as the vagus is functioning, the effect of its stimulation outweighs that of 
the accelerator stimulation, just as normally the vagus tonus is more powerful 
than that of the accelerator (Hering). It is probable that a central accelerator 
stimulation is in part responsible for the acceleration of the pulse which follows 
the primary slowing caused by the medullary stimulants, picrotoxin and cicutoxin 
(Bohm). 

The peripheral actions of drugs on the vagus and the accelerator 
are readily comprehensible if we consider the general principles of 
pharmacological action on the vegetative nervous system. In accord- 
ance with these general principles, it is to be expected that the inhibi- 
tory mechanism will be influenced by those agents which also act on 
the other autonomic nerves, and that the accelerator will be influenced 
by those affecting the sympathetic system. In both vegetative systems 
the seat of action may be in either the nerve-endings or the inter- 
mediate ganglia. 

BIBLIOGRAPHY 

Biedl u. Reiner: Pfliiger's Arch., 1898, vol. 73, p. 385. 

Bohm: Arch. f. exp. Path. u. Pharm., 1876, vol. 5, p. 279. 

Bernstein: Zentralbl. f. d. Med. Wiss., 1867, p. 1. 

Dastre et Morat: Arch, de Physiol., 1885. 

Filehne, W.: Pfliiger's Arch., 1874, vol. 9, p. 470. 

Hering, H. E.: Pfliiger's Arch., 1895. vol. 60, p. 442. 

Kochmann: Arch, intern, de Pharmacodyn. et de Therap., 1905. vol. 16. 

Konow u. Stenbeck: Skand. Arch. f. Physiol., 1889, vol. 1. 

Mayer: Siegm., Sitz.-Ber. d. Wien. Akad. d. Wiss., 1872, vol. 64. 

Mayer, S., u. Freidrich: Arch. f. exp. Path. u. Pharm., 1876, vol. 5, p. 55. 

Verworn: Engelmann's Arch. f. Physiol., 1903, p. 65. 

Drugs Acting on the Vagus in the Periphery. — The same drugs, 
whose specific action on the autonomic nerves has already been learned 
in connection with their action on the intestines, have been found to 
have similar pharmacological actions on the peripheral portion of the 
cardiac vagus, which, as we know, belongs to the cranial autonomic 
system. Thus, it is known of nicotine that it for a time stimulates and 
then depresses the ganglia interposed in the path of the autonomic 
fibres. This is the explanation of that peculiar action on the inhibitory 
cardiac nerves which was first explained by Schmiedebcrg. 

Action of Nicotine on the Frog's Heart. — If a small amount of nicotine be 
administered to a frog, the heart action is soon slowed, in fact it quickly comes 
to a rest in diastole. This stoppage lasts at the most not more than one 
or two minutes, and soon the heart beats again, apparently just like a normal 
one. However, in this secondary stage the inhibitory mechanism behaves in a 
peculiar fashion, for if the vagus nerve trunk be stimulated no slowing occurs. 
If now the sinus be stimulated or muscarine be applied to the heart, it quickly 
stops in diastole and remains quiet. The nicotinized heart thus reacts to mus- 



PHARMACOLOGY OF THE CARDIAC NERVES 247 

carine or to sinus stimulation like the normal organ, but to vagus stimulation 
like an atropinized one. The action of the nicotine must, therefore, have im- 
paired the conductivity of some part of the inhibitory mechanism, a part through 
which the effective vagus stimulation must pass but which lies farther from the 
heart than the point at which sinus stimulation or muscarine acts. This portion 
has been named by Schmiedeoerg the "intermediate portion" (Zwischenstuck) . 
According to the general laws which have been demonstrated by Langley and 
Dickinson for the action of nicotine on the autonomic ganglia, it may be concluded 
that the ganglia interposed in the vagus fibres lie between the vagus trunk and 
its nerve-endings. 

The vagus trunk contains the preganglionic fibres, the stimulation of which, 
according to the rule, is ineffectual after administration of nicotine. Stimulation 
of the sinus affects the post-gangl ionic fibres, whose nerve-endings are acted upon 
by atropine and muscarine but not by nicotine. 

The stellate ganglion is, as it were, a relay station for the accelerator 
fibres, for, after administration of nicotine, the post-ganglionic accelerator fibres 
— which, in the frog and in some of the higher species, pass down in the vagus 
trunk — remain excitable, and, therefore, stimulation of the vagus still causes 
an acceleration of the pulse even after nicotine has been administered (Schmiede- 
berg ) . 

Tobacco Poisoning. — In man, too, the pulse is unusually rapid in 
nicotine poisoning, this being due to prevention of the central vagus 
inhibition, as described above. Later the pulse becomes slower as a 
consequence of the depressing action of nicotine on the automatic 
motor mechanism of the heart. In chronic tobacco poisoning, irregular 
intermittent heart action is frequently observed. Acute tobacco poison- 
ing is, however, not an effect of nicotine alone, for pyridine and a 
number of other toxic substances also play a role in producing the 
effects caused by smoking. The primary slowing and later the 
acceleration of the pulse, the increase of secretions and the increased 
peristalsis, with nausea and vomiting, may, however, be considered 
as due to the nicotine. The same is true of the pallor and faintness 
which are due to central depression. 

Pilocarpine acts in a similar way on the "intermediate portion" 
of the cardiac inhibitory mechanism, causing, in the frog, slower heart 
action and diastolic standstill, which may last for as long as two 
minutes, and is then followed by more rapid heart action {liar nock u. 
H. Meyer). At this stage stimulation of the vagus is ineffectual, but 
direct stimulation of the sinus or application of muscarine to it results 
in a stoppage of the heart. With the higher experimental animals 
the stage of slowing passes even more rapidly. 

Curare and many other drugs have a similar action on these autonomic 
ganglia, but such effects arc produced only by large doses {Langley and Anderson). 

BIBLIOGRAPHY 

Earnack u. II. Meyer: Arch. f. exp. Path. u. Pharm., 1880, vol. 12, p. 3GG. 
Langley and Anderson: Journ, of Physiol., L895, vol. L9, p. 1,39. 

Langley ami Dickinson: dourn. of Physiol., 1890, vol. 11, p. 265. 

Schmiedeberg: Ber. .1. Sachs. Akad. d.'wiss.. is:n, vol. 22, p. 135. 



248 PHARMACOLOGY OF CIRCULATION 

Muscarine and atropine act on the ultimate terminations of the 
vagus (cranial autonomic nerve). 

Muscarine is an alkaloid obtained from one of the common poisonous 
mushrooms, Amanita muscaria, or Agaricus musearius, or fly mushroom. It 
was first isolated by Schmiedeberg in 1SG8. These mushrooms also contain a 
much less poisonous base, choline (Harnack) , which is formed by the decomposi- 
tion of lecithine and which is a constant constituent of many animal tissues, and 
is chemically designated trimethyloxyethyl ammonium hydroxide, 

CH 3 C2H4O 

CH 3 ^N^ 
CH/ \)H 

Muscarine differs from this in its composition only by containing one more atom 
of oxygen, and is probably formed from choline by oxidation. 

In fact, by allowing fuming nitric acid to act on choline, Schmeideberg and 
Harnack prepared an artificial muscarine, which, although similar to, is not 
identical with the muscarine obtained from the fly mushrooms (Bohm, H. Meyer). 
Its pharmacological actions, while resembling those of the natural alkaloid, are 
not entirely the same, for, although the action on the vagus nerve-endings is the 
same, it, on the other hand, causes paralytic phenomena resembling those result- 
ing from the administration of curare. 

Choline also has a pronounced muscarine-like action on the vagus 
nerve-endings, a fact which may be of some physiological significance, 
inasmuch as it has recently been shown that choline is a constant con- 
stituent of many tissues. It may well be that the variable amounts 
present under different conditions may exert an influence on the 
activity of the vagus nerve-endings. 

Muscarine on the Frog's Heart. — If a small amount of muscarine 
be injected into a frog, the heart promptly begins to beat more and 
more slowly, and finally stands still in a state of maximal diastolic 
relaxation, the auricles usually stopping first. This is not due to a 
paralysis of the heart, for any mechanical or electrical stimulation of 
the ventricle causes a prompt contraction. In fact, the heart is more 
susceptible to such stimuli than is normally the case at the end of the 
usual short diastole. The excitability of the motor centres and the 
power of the muscles to contract are both preserved, although inhibited. 
The antagonistic action of atropine shows us the seat of action of this 
peculiar pharmacological effect. It has long been known that stimula- 
tion of the cervical vagus is ineffectual after small doses of atropine 
(v. Bezold, Schmiedeberg) . Similarly muscarine no longer causes a 
slowing or stopping of the heart if atropine has been previously 
applied. 

In the frog's heart muscarine produces the same effect as a con- 
tinuous vagus stimulation. By the electric stimulation of the inhibi- 
tory fibres, the number of beats is lessened, the systolic contractions 
are rendered less complete, and the diastolic distention is increased. In 
certain cases the number of beats is markedly lessened, the pulse 



PHARMACOLOGY OF THE CARDIAC NERVES 249 

volume of the heart remaining about normal, while in other cases the 
heart rate is little affected but the systolic contractions become very 
incomplete. While this holds true for the effects of small doses of mus- 
carine (Cushny), with larger doses the heart rate is always markedly 
slowed and the diastolic relaxation strikingly augmented, or else the 
heart remains permanently relaxed. Muscarine, like vagus stimulation, 
is thus seen to be negatively chronotropic (retarding) and negatively 
inotropic (weakening). 

If the heart of a cold-blooded animal be perfused with a solution containing 
muscarine, the typical slowing and stoppage result, but after a time the heart 
begins to beat again, although at this period the heart contains enough muscarine 
to stop another heart. If, after the heart has begun to beat again, still more 
muscarine be added to the perfused fluid, the same succession of events occurs, 
the heart stopping once more, but after a time beginning to beat again. It is 
thus evident that it is not the presence in the heart of a certain amount of 
muscarine which excites the inhibitory mechanism, but that the stimulus to the 
inhibition is caused by the process of permeation, the muscarine " pressure " 
(Gefiille) (Straub). In the case of other pharmacological actions on the heart — 
for example, that of the digitalis group — the effective factor is not the pressure 
produced during permeation, but is their combination with, specifically susceptible 
elements, — that is, an alteration of physiological conditions. 

Loewi has shown that the negative inotropic effects of muscarine 
may be promptly overcome by calcium salts, while all of its effects are 
promptly suppressed by the smallest doses of atropine, so that the 
heart beats like a normal one, and previous application of atropine 
prevents the development of any muscarine action. 

While a complete suppression of the muscarine action may be effected only 
by the use of atropine, a number of substances which stimulate the cardiac motor 
mechanism cause the diastolic standstill to be interrupted by more or less 
frequent beats. While atropine abolishes all the characteristic changes in 
function produced by muscarine, the diastolic character of the heart action per- 
sists after the incomplete antagonistic effects resulting from the action of these 
other substances, the inhibition continuing, but being interrupted from time to 
time on account of the increased excitation of the motor elements. In this way 
a muscarinized heart may be used as a means of testing a stimulating effect due 
to action on the motor elements. 

BIBLIOGRAPHY 

v. Bezold: Untersuch. d. Physiol. Labor., Wiirzburg, vol. 1. 

Btfhm: Arch. f. exp. Path. u. Pharm., 1885, vol. li), p. 87. 

(ushnv: Arch. f. exp. Path. u. Pharm., 1893, vol. 31, p. 431. 

Earnack: Arch. f. exp. Path. u. Pharm., 1875, vol. 4, p. 168. 

Loewi: Zentralhl. f. Physiol., 1905, vol. 19, p. 593. 

Meyer, II.: Arch. f. exp. Path. u. Pharm., 1893, vol. 32, p. 101. 

Bchmiedeberg: Ber. d. Sachsisch. Ges. d. Wiss., 1870. 

Bchmiedeberg u. Earnack: Arch. f. exp. Path. u. Pharm., 1870, vol. 6, p. 101. 

Bchmiedeberg U. Koppe: Das giftige Alkaloid des Fliegenpilzes, Leipzig, 1809. 

Straub: Pfltiger'B Arch., 1907, vol. 119, p. 127. 

Atropine. — Small doses of atropine have as their sole cardiac 
action that of depressing Ihose vagal nerve-end in<rs which are stimu- 
lated by muscarine. According to Harnack and Eafemann, 1/50 mg. 



250 PHARMACOLOGY OF CIRCULATION 

to 50 cm. of perfusion fluid is sufficient to produce this result, so that 
it is then impossible to cause inhibition of the heart by either vagus 
or sinus stimulation, or by muscarine, nicotine, or pilocarpine. In 
other respects the heart behaves normally. The following curve shows 
the effects of small doses of atropine in overcoming the muscarine 
standstill of the frog's heart, suspended according to the method of 
Gaskell and Englemann: 

K Muscarine normal 



Fig 21. — Suppression of the muscarine standstill by atropine. Read from right to left. 

In addition to their depressing action on the inhibitory mechanism, larger 
doses of atropine would appear also to exert stimulating effects on the motor 
mechanism of the heart. In Langendorff' s experiments, atropine exerted a 
positively chronotropic influence on the secondary automatic motor centres which 
lie in the apex of the frog's heart. After functional separation from the higher 
controlling centres by clamping, the apex under ordinary conditions remains 
inactive. After application of atropine, however, contractions of the apex may 
occur spontaneously, or a mechanical stimulus causes a long series of beats, 
although an unatropinized apex responds to each stimulus with but one eon- 
traction. We are dealing here with an exciting action of atropine in doses which 
are many times larger than those which completely paralyze the inhibitory 
apparatus (Hcdbom) . The often-claimed suppression, by such larger doses, of 
the standstill of the heart, due not to inhibition, but to paralysis of the motor 
mechanism (Luchsinger) , does not affect the value which small doses of atropine 
possess as a certain test for inhibitory actions. A standstill of the heart or a 
slowing of the pulse which is removed by small doses of atropine is due to 
inhibition. 

The stimulation of the cardiac inhibitory mechanism by muscarine 
and its depression by atropine occur also in the mammal, in a fashion 
quite analogous to the above-described effects on the frog's heart. 
Stoppage of the heart or an extreme slowing of the pulse by muscarine 
necessarily, however, causes much more violent symptoms in the warm- 
blooded animal, on account of the secondary effects resulting from 
disturbed circulation. After a muscarine injection the aortic pressure 
sinks rapidly (Pig. 22). During the longer or shorter diastolic pauses 
the heart is maximally distended, only incomplete contractions inter- 
rupting the standstill. Inasmuch as the blood cannot pass from the 
greater veins into the overfilled auricles, the blood accumulates in the 
pulmonary system, and dyspnoea must quickly result, for the over- 
filling of the pulmonary vessels interferes with the air-change and 
at the same time the circular muscles are tonically contracted. The 
asphyxia must quickly prove fatal if a dose of atropine does not 
relieve it. Atropine may also overcome the marked pulse slowing, 
and if the heart has not been too much harmed by the asphyxia it 
quickly recovers. Previous section of the vagi causes no alteration 
in the phenomena resulting from the administration of the muscarine. 



PHARMACOLOGY OF THE CARDIAC NERVES 

3' 



251 



Of importance in connection with 
the poisoning produced by the fly 
mushrooms is a base resembling 
atropine (Schmiedeberg) , as well as 
another poison still imperfectly in- 
vestigated, which produces symptoms 
of excitation of the central nervous 
system and which is found chiefly 
in the fresh mushrooms (Harmsen) . 
[A glucoside studied by Ford and 
Abel and possessing many interest- 
ing properties would appear also to 
be of considerable importance in 
this connection. — Tr.] As a result 
of the combined action of these dif- 
ferent poisons, the symptoms of 
mushroom poisoning differed mark- 
edly from those observed in poisoning 
by pure muscarine in the animals. 

Muscarine Poisoning. — The symptom 
complex of muscarine poisoning results 
from its actions on the stomach and intes- 
tines, already described in a previous sec- 
tion, and from those on the eye and on the 
secretions, and especially from the actions 
on the circulation which threaten the life 
of the victim. It is especially well devel- 
oped in the cat. The first symptoms — 
namely, chewing and licking movements, 
with flow of saliva — develop within a few 
minutes after the subcutaneous injection 
of several milligrammes. Active peri- 
stalsis, retching, vomiting, defecation, and 
tenesmus ensue, as well as contraction of 
the pupil, leading perhaps to its complete 
disappearance. The pulse becomes ex- 
tremely slow, marked dyspnoea develops, 
and the animal can no longer maintain the 
upright position, but falls on its side, death 
with light convulsions resulting from stop- 
page of the respiration at a time when 
occasional heart-boats still occur. Atro- 
pine may rescue the animal, oven in ox- 
tn-niis.and tins drug is probably the proper 
antidote in mushroom poisoning in man. as 
well as in poisoning by certain little- 
known ptomaines formed during putrefac- 
tion, which have a muscarino-Iike ad ion. 



PnvsoRTiGMiNE. — During o u r 
study of the action of physostiginine 
on the intestines and on the pupils, 
wo have learned that it is a drug 

which stimulates vagus nerve-endings 



252 PHARMACOLOGY OF CIRCULATION 

(Winterberg) and slows the pulse. As this effect is not completely sup- 
pressed by atropine, it follows that physostigmine must act on the heart 
at a different point from atropine, but the situation of this point has 
not yet been definitely determined (Winterberg, E. Harnack). 

Actions on the Accelerator in the Periphery. — The nerve- 
endings of the accelerator nerves are part of the sympathetic system, 
and, like all the nerve-endings of this system, they too are stimulated 
by epinephrin. Cocaine's similar behavior toward the sympathetic 
system has already been discussed, and the acceleration of the pulse 
at the commencement of the cocaine action has been recognized as 
a side action of this drug. The influence of epinephrin on the 
intracardiac accelerator nerve-endings appears clearly in the isolated 
heart prepared according to Langendorff 's method. Its effects on the 
intact circulation are complicated by the retardation of the pulse 
resulting from the already-mentioned stimulation of the vagus centre. 
In fact, at the start this slowing preponderates. 

The increase in pulse-rate after the administration of caffeine or 
theobromine is also due to excitation of the accelerator nerve-endings. 
This may be seen in susceptible individuals after drinking strong 
coffee. 

It may further be stated that it is not possible to differentiate 
between actions on the accelerator nerve-endings and the alterations 
in function of those mechanisms in the heart which we have defined 
as the "stimulus-producing mechanisms," and which from now on 
will, in the interest of brevity, be spoken of as the "motor centres." 
These centres in the heart are either identical with the accelerator 
nerve-endings — II. E. Bering was able by stimulation of the accelerator 
to cause the dog's heart, perfused according to Langendorff, again to 
beat automatically after it had entirely ceased to beat — or at least 
we are unable at present to distinguish between the accelerator nerve- 
endings and the motor apparatus of the heart. For these reasons the 
above-discussed pharmacological actions on the terminal portions of 
the accelerator nerves must also be considered as actions on the motor 
centres of the heart. 

BIBLIOGRAPHY 

Harmsen: Arch. f. exp. Path. u. Pharm., 1903, vol. 50, p. 361. 
Harnack, E.: Ztschr. f. exp. Path. u. Therap., 1908, vol. 5. 
Hedbom: Skand. Arch. f. Phvsiol.. 1899, vol. 9, p. 1. 
Hering, H. E.: Pfliiger's Arch., 1905, vol. 115, p. 354. 
Luchsinger: Arch. f. exp. Path. u. Pharm., 1881, vol. 14. 
Schmiedeberg: Arch. f. exp. Path. u. Pharm., 1881, vol. 14, p. 376. 
Winterberg: Ztschr. f. exp. Path. u. Therap., 1907, vol. 4. 

CARDIAC DEPRESSANTS 
The number of these is legion. In them are included, among others, 
the narcotics of the aliphatic series, of which those containing halogen 
are distinctly more harmful to the heart than those containing no 



CARDIAC DEPRESSANTS 253 

halogens. Using the isolated frog's heart, Dieballa has investigated 
quantitatively the activity of the different members of this group, and 
has ascertained that chloroform exceeds in its heart-depressing action 
all the other members of this group which were investigated. In order 
to produce the same cardiac effects as produced by chloroform, it is 
necessary to use of ethyl bromide 12 times the molecular concentration, 
of ether 48 times, and of alcohol 132 times. Bock's experiments with 
the "heart-lung-circulation" resulted in an equally indisputable 
demonstration of the enormous difference in the toxicity for the heart 
of chloroform and ether. 

Numerous other substances belonging to different pharmacological 
groups have a similar power of causing retardation of the pulse and 
depression of the heart, which results finally in stoppage of the heart 
in diastole. According to Brandenburg, the salts of the bile acids must 
be included here, although* these slow the heart also through action 
on the vagus centres {Loewi, Weintraud) . With more pronounced 
pharmacological action, however, they directly affect the production 
of stimuli in the heart. This is of importance in connection with the 
slowing of the pulse in icterus, as this must be attributed to their 
direct cardiac depressant action as well as to the central stimulation 
of the vagus produced by them. Atropine usually overcomes the 
pulse-slowing in icterus, as was demonstrated by Weintraud in a series 
of cases. This, however, does not exclude the possibility that a 
depression of the motor apparatus, which, is not influenced by 
atropine, may occur clinically as a second component of the toxic, 
action resulting from the presence in the blood of larger amounts of 
these salts, just as is the case when either the frog's or the isolated 
mammalian heart is poisoned by larger doses. 

With the aid of atropine it is possible to distinguish between 
pulse-slowing due to stimulation of the inhibitory mechanism and 
that resulting from depression of the motor mechanism. On the 
other hand, it is much more difficult to differentiate between a depres- 
sion of the automatic motor centres in the heart and a depression of the 
contractile power of the cardiac muscles. Negative chronotropic and 
negative inotropic pharmacological actions usually go together, and 
soon after the cessation of its automatic activity the heart loses its ex- 
citability to mechanical, electrical, and chemical stimuli. This is the 
case, for example, after large amounts of quinine (Santesson) . The 
potassium salts are also typical cardiac depressants if under certain 
conditions (intravenous injections or subcutaneous administration of 
very large quantities) their concentration in the blood is increased 
beyond 0.08 per cent. (Tetens). In this case, too, loss of excitability 
of the muscles follows quickly on the cessation of contractions. 

Chloral hydrate is a type of the cardiac depressants. Under its 
influence the heart beats slower and slower, and during its prolonged 
diastole is more relaxed and distended than normally. Shortly after 



254 PHARMACOLOGY OF CIRCULATION 

stoppage in diastole has occurred, each mechanical, chemical, or elec- 
trical stimulus results in a contraction, but atropine does not over- 
come this standstill. In their physiological analysis of this progressive 
pulse-slowing, Harnack and Witkowski were able to determine that 
the seat of action of the paralysis lay in the automatic mechanism of 
the heart, for the rate of the whole heart was slowed by painting the 
sinus with chloral or the similarly acting iodal. Later a depression 
of the power of contraction also occurred. It is thus seen that the 
primary action of chloral hydrate is negatively chronotropic, and, 
more weakly and usually somewhat later, it is also negatively inotropic. 
The excitability and the conduction of stimuli are less affected 
(Bohme), and it may in general be said that all these depressants 
mentioned influence the inotropic properties {contractility), the oath- 
motropic (irritability) , and the dromotropic {conductivity of stimuli) 
functions qualitatively alike, but quantitatively in different degrees, 
wit ile their effects on the chronotropic function (production of 
stimuli) folloiv special rules. 

There can be no doubt that there exist in the heart special mechanisms for 
the production of stimuli, and that these mechanisms may be affected by specific 
pharmacological actions. It makes no difference whether this function is attrib- 
uted, in accordance with the neurogenic hypothesis, to nervous elements or to a 
special type of muscle-cells, as demanded by the myogenic hypothesis. All the 
characteristic functional properties of the cardiac muscle are found also in the 
apex of the heart, in which under usual conditions the capacity for the inaugura- 
tion of stimuli is lacking, and which, therefore, under normal conditions remains 
at rest when, by clamping, it is physiologically isolated from the upper portion 
of the heart. However, it contains a mechanism for the conduction of stimuli, 
for an artificial stimulus at any point causes a simultaneous contraction through- 
out its whole extent. It also has a refractory period, and in the apex, just as 
in the intact heart, the strength of the contraction is independent of the intensity 
of any stimulus strong enough to be effective. Chloral hydrate almost com- 
pletely abolishes these characteristic functions of the apex, while its suscepti- 
bility to single electrical stimuli as well as the function of conduction of stimuli 
persists, so that the heart apex still contracts as a whole after each efficient 
minimal stimulus. Inasmuch as the power of inaugurating stimuli is paralyzed 
throughout the whole heart simultaneously with these effects on the character- 
istic attributes of the cardiac function, the heart under these conditions resembles 
in its behavior a portion of intestine (Magnus) or a Limulus heart (Carlson). 
whose nervous motor centres have been anatomically separated from the muscles. 
In analogy with the above-mentioned examples, there is ground for concluding 
that by the use of chloral hydrate, a drug that in general paralyzes nervous 
centres sooner than nerve-fibres and muscles, we have succeeded in functionally 
eliminating those physiological properties of the heart, which are dependent 
on nervous centres or ganglia ( Rohde ) . 

BIBLIOGRAPHY 

Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 158, and vol. 43, p. 367. 

Bohme: Arch. f. exp. Path. u. Pharm., 1905, vol. 52, p. 346. 

Brandenburg: Engelmann's Arch., 1903, Suppl., p. 150. 

Braun u. Mager: Wien. Akad. Ber., 1899, vol. 108, p. 599. 

Carlson: Am. Journal of Physiol., 1904, vol. 12, and 1905, vol. 13. 

Dieballa: Arch. f. exp. Path', u. Pharm., 1894, vol. 34, p. 137, and vol. 45, p. 367. 

Harnack u. Witkowski: Arch. f. exp. Path. u. Pharm, 1879, vol. 11, p. 1. 

Harnack: Engelmann's Arch., 1904, p. 415. 



CARDIAC STIMULANTS 255 

Hedbom: Skand. Arch. f. Physiol., 1899, vol. 9, p. 1. 

Lowit: Zeitsehr. f. Heilk., 1882, p. 459. 

Magnus: Pfiiiger's Arch., 1904, vol. 103. 

Rohde: Arch. f. exp. Path. u. Pharm., 1905, vol. 54, p. 104. 

Santesson: Arch. f. exp. Path. u. Pharm., 1893, vol. 32, p. 321. 

Tetens, Hald: Arch. f. exp. Path. u. Pharm., 1905, vol. 53, p. 227. 

Weintraud: Arch. f. exp. Path., vol. 34, p. 37. 

CARDIAC STniULANTS 

Stimulation of the motor mechanism of the heart is of the greatest 
therapeutic importance, for narcotic poisons or the toxins of infection 
may and frequently do functionally depress the heart to such an 
extent that a collapse of cardiac origin develops. In such case it is 
important to help the heart over a temporary period of inefficiency, 
as, if under the influence of a stimulant it heats better for even a 
short time, thus bringing about a higher pressure in the aorta, its own 
nutrition is improved, and it may thus be enabled to escape the death 
threatened by the poisoning. 

Camphor. — In the pathological disturbances spoken of as acute 
failure, camphor is the stimulant most used, although on the normal 
heart the favorable action of camphor cannot be demonstrated with 
certainty. While it is true that a strengthening of the beats of a 
strongly beating frog's heart may be observed (Heubner, Baum, 
Maki) if the dose has, by good fortune, been properly determined, 
often such effect is not apparent {Alexander-Levin) . Moreover, only 
in certain cases does camphor produce an improvement in function 
in the cat's heart perfused according to Langendorff 's method (Selig- 
mann). On the other hand, in pathologically weakened hearts it 
proves itself in incontrovertible fashion to be a stimulant to the 
automatic motor mechanism, increasing the frequency and the power 
of the heart-beat. 

It can be especially well shown on the frog's heart that camphor 
can overcome a condition of standstill. As a result of stimulation of 
the motor mechanism, the inhibition is interrupted or the paralytic 
standstill resulting from narcosis of the motor centres is overcome. 

If a heart which has been stopped by muscarine is exposed to camphor vapor 
or to NaCI solution containing minimal quantities (1-1000) of this drug, more 
or less frequent pulsations interrupt the standstill (Harnaclc u. Witkowski) . 
while ;if the same time the persistence of the inhibition is evidenced by the 
well-marked diastole of the heart. Camphor, being a chemical stimulant for the 
motor centres, is able to overcome the inhibition, just as during a muscarine 
standstill each mechanical stimulation excites a contraction. 

Camphor acts also as a direct antagonist to the depressant poisons. 
At a lime when, for example, the (-Moralized heart is beating with 
extreme slowness, the application of camphor starts it beating more 
rapidly and the contractions become more powerful. 

Even some minutes after the heart has ceased to beat camphor can start 
it. beating again [Boh/me). This reviving action may be most clearly shown on an 

isolated and perfused frog's licni't poisoned by elilnrnl. by adding camphor to the 



256 PHARMACOLOGY OF CIRCULATION 

perfusion fluid which already contains chloral. Although the heart may already 
be severely poisoned by chloral and continues to be subjected to its action, after 
camphor is added to the perfusion fluid the heart action is at once improved and 
the frequency and strength of the contractions are both increased. (Fig. 23.) 

Camphor is thus able to revive the motor mechanism of the heart 
at a time when the automatic centres are threatened with extinction. 
As this automatic mechanism acts under ordinary conditions with 
maximal efficiency, the favorable action of camphor cannot be well 
observed on a normal heart. 

The above-cited actions have been well established for the frog's heart, 
and it may be considered as proved that camphor will exert the same effect on 
the pathologically disturbed automatic centres in the hearts of the higher species. 
However, the experimental demonstration of this is much more difficult in mam- 
mals, for in them it is not so easy to bring about a stationary condition of 
disturbed heart function or to study the actions of drugs thereon. 



_JL 



After chloral has acted 
for 20 minutes 



During perfusion with chloral and camphor. 
A-A-JULJU'L./i UAAAAJULAJMAAM 



Two minutes later Ten minutes later 

Fig. 23. — Suppression of chloral standstill by camphor in a perfused frog's heart 

Camphor possesses further a distinct action in cases of a peculiar 
disturbance of the heart functions known as fibrillation. By this term 
is understood the violent but fully uncoordinated contractions of the 
whole reticulum of the cardiac muscles, a condition which may be 
induced in the living heart by sudden interruption of the coronary 
circulation, as also by acute poisoning with chloroform and other 
toxic substances. Fibrillation may also be readily induced in the sur- 
viving heart by direct stimulation with the induced current, such 
stimulation causing the surviving cat's heart to fibrillate either per- 
sistently or for some time. If, however, to the usual perfusion fluid 
small amounts of camphor be added and the perfusion be continued, 
the fibrillation ceases, and renewed stimulation with the induction 
current causes only momentary fibrillation (Seligmann, Gottlieb, 
Klempercr, opposed by Winterberg) . 

Suppression of the fibrillation may account for the therapeutic 
effect of camphor in cases where the auricle alone is affected. Fibril- 
lation of the ventricle must quickly cause death, on account of the 



CARDIAC STIMULANTS 257 

interruption of the circulation resulting from it. On the other hand, 
in man cases are observed with very rapid and irregular pulse, present- 
ing a clinical picture which Cushny and Edmunds have shown to re- 
semble closely the phenomena observed in dogs when fibrillation of the 
auricles alone has been induced. In such cases, as soon as the auricle 
begins to beat regularly again, the ventricular pulse also becomes 
normal. The heart action during the death struggle, which is often 
improved by camphor, presents certain analogies with this condition. 

From the above it is clear why the normal blood-pressure will not 
be raised by any action of camphor on the heart, although it is raised 
by doses which cause convulsions, this being due to stimulation of 
the vasomotor centres. Only when the circulation is depressed may 
a rise in blood-pressure result from doses not large enough to cause 
convulsions. The role played here by an improvement of the vessel 
innervation will be discussed later. There is no doubt that when 
camphor is used to revive the circulation in dying patients, in whom 
the automatic centres in the heart are failing, it may exert a direct 
favorable action on the heart* 

Musk was formerly much used for the same indications as camphor, 
but to-day it is used but seldom and is no longer officinal. There 
are no experimental investigations which would justify its use 
clinically. 

BIBLIOGRAPHY 

Alexander-Levin: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 226. 

Baum: Zbl. f. d. med. Wiss., 1870, vol. 8. 

Bernstein: Engelmann's Arch., 1906, Suppl., p. 343. 

Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 158. 

Bohme, A.: Arch. f. exp. Path. u. Pharm., 1905, vol. 52, p. 346. 

Carlson: Am. Journ. of Physiol., 1906, vol. 17. 

Cushny and Edmunds: Am. Journal of the Medical Sciences, 1907, new series, 

vol. 133, p. 66. 
Gottlieb: Ztschr. f. exp. Path. u. Ther., 1905, vol. 2, p. 385, and 1906, vol. 3, p. 588. 
Bamalinen, J.: Skand. Arch. f. Physiol., 1908, vol. 21, p. 64. 
Harnack u. Witkowski: Arch. f. exp. Path. u. Pharm., 1876, vol. 5, p. 401. 
Heubner: Arch. f. Heilk.. 1870, vol. 9. 

Klemperer: Ztschr, f. exp. Path. u. Ther., 1907, vol. 4, p. 389. 
Maki: Diss., Strassburg, 1884. 

Seligmann: Arch. f. exp. Path. u. Pharm., 1905, vol. 52, p. 333. 
Winterberg; Pfluger'e Arch., 1903, vol. 94, p. 455. 
Winterberg: Ztschr. f. exp. Path. u. Ther., 1906, vol. 3, p. 182. 

Ether. — The subcutaneous injection of ether is often employed 
as a cardiac analeptic (restorative), although it has not been possible 
to demonstrate that ether possesses a direct stimulating effect on the 
heart's activity. Although in conditions of collapse temporary im- 
provement of the circulation may follow the subcutaneous injection 
of ether, this is, in part at least, to be attributed to the sensory stimu- 
lation caused by the powerful and, in conscious patients, very painful 

* [Recently Heard (Am. J. of Med. Sci., 1031. vol. 135. p. 238) in a carefully 
conducted clinical investigation has failed to note any favorable effects on the 
circulation following the administration of camphor. — Tic. J 
17 



258 PHARMACOLOGY OF CIRCULATION 

irritation of the tissues which, the injection causes. Its reflex effects 
on the respiration and circulation must, therefore, be considered as 
similar to those arising from other sensory stimuli. They may, in 
combination with the vasomotor effect of ether, contribute to the im- 
provement of the blood-pressure and thus to a better flow of blood 
through the heart. 

In ether narcosis the frequency of the pulse is regularly increased, 
in adults often to above 100, in children even more so. In experi- 
ments on animals also, the pulse frequency is regularly increased 
by the inhalation of not too concentrated ether vapor {Elf strand), 
an effect quite contrary to that caused by chloroform. This, however, 
is not to be attributed to a direct effect on the heart, for this accelera- 
tion does not occur if the heart be isolated from the central nervous 
system (Bock). It is, therefore, of central origin, as the result of either 
direct or reflex actions on the centres of the extracardial nerves. This 
acceleration of the pulse must aid in producing the rise in blood- 
pressure observed at the commencement of narcosis. The action of 
ether on the heart may, therefore, be interpreted only as an indirect 
one, for up to the present time there exists no proof that it possesses 
a direct favorable action. 

BIBLIOGRAPHY 

Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41. p. 158. 
Elfstrand: Arch. f. exp. Path. u. Pharm., 1900, vol. 43, p. 435. 

Alcohol. — It is a still much-discussed question whether alcohol 
exerts a direct stimulating action on the heart. Even the behavior 
of the pulse has been differently determined and interpreted by dif- 
ferent observers. As a rule, in man alcohol accelerates the pulse 
(John), but in carefully conducted experiments this has at times 
not been the case (Zimmerberg, Wendelstadt). There is no doubt 
that the acceleration of the pulse, when it does occur, is, at least in 
part, due to secondary effects of the action of alcohol on the mind, 
as well as to reflexes caused by its smell and taste or by its local 
action on the gastric mucous membrane. Recently Dixon observed 
that acceleration of the pulse did not occur after absorption of alcohol 
from the stomach if it were introduced highly diluted, and that, when 
20 per cent, alcohol was held in the mouth for only a short time and 
then spit out, this acceleration passed off more quickly than when 
the alcohol was swallowed. In experiments on animals, secondary 
effects resulting from actions on the central nervous system are 
apparent even after intravenous injection. For these reasons, only 
experiments on the isolated organ are suitable for the determination of 
the extent to which a direct stimulant action on the motor mechanism 
of the heart is responsible for the acceleration of the pulse. The same 
holds good for the effects on the strength of the contractions. 



ALCOHOL AND THE HEART 259 

Experiments on the isolated heart indicate that, beginning with a 
concentration of about 1 per cent., alcohol exerts a distinctly harmful 
influence on the cardiac function (Loeb). According to many 
authors who have subjected the isolated frog (Dreser, Dieballa) or 
mammalian heart (Bock, Tunnicliffe and Rosenheim, Kochmann) to 
the influence of even weaker solutions, only a depressant action is 
exerted, and all favorable action is denied. On the other hand, Loeb, 
using even smaller amounts of alcohol, observed a distinct although 
slight stimulant action on the surviving cat's heart perfused according 
to Langendorff. This favorable effect was obtained by the use of 
from 0.13-0.3 per cent, alcohol, and was especially marked in such 
hearts as were previously beating poorly. A favorable influence was 
also obtained as an after effect of stronger concentrations after the 
alcohol-containing blood had been washed out. Wood and Hoyt pro- 
duced an unmistakable increase of the pulse volume of the frog's 
heart by adding 0.25-0.5 per cent, alcohol, and Dold obtained similar 
results. Nevertheless, the differences observed in the mammalian 
experiments were only slight ones and the results were by no means 
constant. This seems to indicate that the normal heart working under 
favorable conditions is but slightly influenced by small amounts of 
alcohol (just as we saw similar conditions obtaining for the action of 
camphor), and that only the feeble contractions observed during 
depressed cardiac activity are favorably influenced by suitable doses 
of alcohol. This is evident from Dixon's experiments. In these ex- 
periments, conducted on mammalian hearts perfused with Ringer's 
solution, with or without the addition of dextrose, the strength of the 
contractions was usually increased when the fluid contained 0.05-0.3 
per cent, of alcohol. This positive effect was, however, much more pro- 
nounced in hearts which had previously been kept beating for hours 
without any addition of organic nutrient material to the perfusion 
fluid, while this effect was either much slighter or was entirely lacking 
in hearts which were beating strongly and which had been kept well 
nourished through the addition of glucose to the perfusion fluid. 
Stronger concentrations of alcohol strengthened the heart's action 
only temporarily, and quickly produced harmful results. 

Some grounds for the belief that alcohol serves the heart as a 
nutrient material are found in the fact that the alcohol produces a 
much more pronounced stimulation in badly nourished hearts than 
in hearts which had been kept beating in a nutrient solution containing 
glucose but no alcohol. This drug easily passes into all tissues, and 
the experiments of Dixon make it probable that it may be used as 
;i source of energy. In fact, a part of the alcohol added to the per- 
fusion fluid is consumed (Ilamill). Moreover, according to Dixon, 
glucose improves Hie action of the heart quilt; similarly to alcohol, 
and is also consumed when perfused through the active mammalian 
hearl (Johannes Mutter, Locke and Rosenheim). 



260 PHARMACOLOGY OF CIRCULATION 

BIBLIOGRAPHY 

Bock, A.: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 173, here literature. 

Dieballa: Arch. f. exp. Path. u. Pharm., 1894, vol. 34, p. 137. 

Dixon: Journ. of Physiol., vol. 35. 

Dold: Inaug. Diss., Tubingen, 1906. 

Drescr: Arch. f. exp. Path. u. Pharm., 1887, vol. 24, p. 236. 

Hamill: Journ. of Phvsiol., 1910, vol. 39, p. 476. 

John: Ztschr. f. exp. Path. u. Ther., 1909, vol. 5. 

Ivochmann: Arch, de Pharmacodyn. et de Ther., 1904, vol. 13, p. 329. 

Locke and Rosenheim: Journ. of Physiol., 1904, vol. 31. 

Loeb: Arch. f. exp. Path. u. Pharm., 1895, vol. 52, p. 459. 

Miiller, Johannes: Ztschr. f. allg. Physiol., 1904, vol. 3. 

Tunnicliffe and Rosenheim: Journ. of Physiol., 1903, vol. 29. 

Wendelstadt: Pniiger's Arch., 1899, vol. 76, p. 233. 

Wood and Hoyt: Memoirs of National Acad, of Sciences, 1905, p. 10. 

Zimmerberg: Inaug. Diss., Dorpat, 1869. 

Epinephrin is a typical stimulant to the heart's activity. 

The stimulation of the accelerator nerve-endings manifests itself 
especially in the surviving mammalian heart by acceleration of the 
heart rate and by a striking increase in the strength of the contractions. 
This effect, in contradistinction to that of camphor, also occurs on 
hearts which are beating well and are well nourished. 



Epinephr 

1 



'im§m§k 



Fig. 24. — Effect of epinephrin on the isolated cat's heart. 

Through its specific power of stimulating the vasomotor nerve- 
endings in the vessel walls, epinephrin, when injected intravenously, 
causes a general vasoconstriction and an enormous rise in blood- 
pressure. Such an increased resistance in the vessels lays upon the 
heart a great burden while it is emptying itself. Because of this 
preponderance of the action upon the vessels, it may happen that 
the heart breaks down as a result of the rise in blood-pressure, but, 
when epinephrin is injected into a depressed circulation, the blood- 
pressure need not rise above the normal, and then the increased power 
of the heart's contractions is clearly apparent. 

That this is not the result simply of the indirect effect of improved 
blood flow in the heart, but that it is due to a direct action on the 
heart, is shown by experiments in which the heart has first been 
brought to a standstill by chloral hydrate, chloroform, or potassium 
salts, or else has been so depressed that it is beating very feebly and 
infrequently. If then epinephrin be injected into the veins and reaches 
the heart, the heart revives again and beats more frequently and more 
powerfully than at the start. 

As the epinephrin is distributed around in the circulation by 
the restored activity of the heart and is thus able to act on the vessels, 



EPINEPHRIN AND THE HEART 261 

the blood-pressure rises again very markedly, even if it had previously 
sunk to the zero point. This reviving action of epinephrin is, however, 
very fleeting, because this drug is very unstable when injected into 
the circulation. However, the favorable results may outlast its fleet- 
ing action in case the cause of the fall in pressure — for example, 
chloroform or potassium salts — has in the meantime been eliminated. 
In animal experiments, in eases of apparent death caused by chloro- 
form, it is possible by the use of epinephrin to start the heart beating 
again.* 

This cardiac action of epinephrin may be demonstrated in the 
isolated "heart-lung" circulation. With the heart under these con- 
ditions beating independently of all influences from the central ner- 
vous system, the frequency of the pulse increases simultaneously with 
the strengthening of the contractions. On the other hand, in the 
intact circulation the pulse is at first slow, for the rise in blood- 
pressure causes a central vagus stimulation, which overcomes the 



Injection 



^/-■yvVV/vW<tyW* 



>jT_rw-ij-ixT-r-iJi-rij-ij-i-ri-rT-iajT-rvr\ri_iaj^^ 

Fig. 25. — Effect of the injection of suprarenal extract 1 minute and 35 
seconds after cessation of heart-beat. 

tendency of the heart to contract more rapidly as a result of the 
direct action on the heart. Only later does the excitation of the motor 
mechanism of the heart gain the upper hand so that the heart may 
beat more rapidly. 

BIBLIOGRAPHY 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 99, and 1899, vol. 43, 

p. 286. 
Oliver and Schaier: Journ. of Physiol., 1895, vol. 18. 

THE ACTION OF DIGITALIS ON THE HEART 
The members of the pharmacological groups of digitalis and caf- 
feine are also cardiac stimulants, influencing the contractions of the 
heart in characteristic and, for each group, different fashion. 

The active principles of the digitalis leaves and a number of other 
glucosides occurring in very different species of plants, all produce 
a similar typical effect on the activity of the heart. Digitalin and 
digitoxin, derived from the digitalis leaves, and strophanthin, derived 
from strophanthus seeds, are the most important members of this 
group. Their typical action is characterized by an especially elective 
action on the heart, which is well shown during the development of the 



BUnpl 



1 [Also in human beings, particularly if the action of the epinephrin be 
lemented by massage <>f the heart. — Tb.] 



262 PHARMACOLOGY OF CIRCULATION 

digitalis action on the heart of a frog. At a time when this organ, 
having passed through all phases of the poisoning, has been brought 
to a complete standstill, the frog shows no symptoms of toxic action 
on his nervous system, and, inasmuch as the nervous system of cold- 
blooded animals preserves its excitability for a considerable period 
after cessation of the blood flow, the frog is still able to hop around 
quite normally. 

In the following discussion the substances belonging to the pharma- 
cological group of digitalis will be spoken of, for the sake of brevity, 
as digitalis bodies, or substances, although typical members of this 
group occur in other plants. 

Action on the Frog's Heart. — If a full dose of a digitalis body 
be injected into a Rana temporaria, the following phenomena may be 
observed on the exposed heart (Bohm). After some minutes the 
relaxation appears to be increased, and to last somewhat longer than 
normally. The frequency of the beats is slightly diminished, while 
the contraction is more energetic, — that is, the ventricle at the 
height of its contraction is paler than it was before administration of 
the drug, as it drives out its contents more completely. Then there 
occur occasional temporary diastolic pauses, and later the movements 
of the heart become strikingly irregular, owing to the fact that all 
portions of the ventricle are no longer equally relaxed in each diastole. 
As these partial diastoles of the different parts of the ventricle do 
not occur with any regularity, the blood is shoved hither and thither 
in the heart, and the peculiar picture of "heart peristalsis" develops. 
This phase, which is often interrupted by a series of regular heart- 
beats, is succeeded sooner or later by a persistent contraction of the 
ventricle (systolic standstill), which represents the characteristic final 
stage of the pharmacological action. The ventricle remains completely 
contracted and emptied of blood, while the auricle, distended with 
blood to bursting, continues to beat for some time, finally passing 
into a condition of stoppage in diastole. Even after the heart has 
passed into the phase of systolic standstill, it has by no means lost 
its power of beating, but the tendency of the ventricle to remain in a 
contracted condition prevents its relaxation. If at this stage relaxa- 
tion is artificially brought about through hydrostatic pressure, this 
forced diastole is followed by a series of active heart-beats (Schmiede- 
berg). This standstill is, therefore, at the beginning to be con- 
sidered as due to a persistent stimulation of the contracting mechan- 
ism and not as due to a paralysis. However, the' cardiac muscle finally 
becomes unexcitable and dies in a state of contraction. 

A closer analysis of the characteristic course of this poisoning is 
especially interesting, for these first actions on the frog's heart 
exhibit features of that digitalis action which is of importance in its 
therapeutic application. Such closer analysis is possible only on the 
isolated heart, for the heart acting in conjunction with the whole 



DIGITALIS AND THE HEART 263 

circulation is influenced by secondary factors, — for example, by the 
changing inflow of blood from the vessels. 

It, therefore, was significant of a decisive advance in our knowl- 
edge of digitalis when Bohm, in 1872, and, later and more completely, 
Williams investigated the actions of the digitalis bodies on the frog's 
heart beating in an artificial circulation. It was shown by this author 
that the diastolic relaxation was increased quite independently of any 
retardation of the rate, the ventricle relaxing to a greater extent 
under an unchanged diastolic pressure, while the systolic contractions 
pump out this greater content very completely. The pulse volume of 
the heart, therefore, increases, as does the pulse pressure in the arti- 
ficial circulation, and thus the "heart work" accomplished by each 
contraction is increased, as is also the work done per minute, unless 
the rate of the heart-beats is too greatly diminished. 




wvwwvw 

Normal 10 min. after helleborein 10 minutes later IB min. later. Standstill 

Fig. 26. — Tracing from frog's heart (Williams). 

In this first phase the digitalis bodies produce two effects on the 
cardiac function by a "systolic" and a "diastolic" action. The 
"diastolic" action expresses itself in the retardation of the heart's 
action and in the increase of the relaxation. The "systolic" action 
has its expression in the more complete and energetic pumping out 
of the ventricular contents. The heart under the influence of digitalis 
works like a pump, the piston of which at each stroke is raised higher 
and pushed in again more completely. The absolute power of the 
heart, however, is unchanged, — that is, the piston of the pump is 
not more forcibly moved nor is it able to overcome any higher 
pressure than before. The heart does not gain in muscular power, 
but simply utilizes its power more efficiently. 

The slowing of the frog's heart which is caused by digitalis occurs quite 
independently of the vagus centre and of any action on the vagus nerve-endings. 
While previous atropinization produces no effect, still the "diastolic" digitalis 
action resembles to a marked degree the vagus inhibitory action, and actually 
finally causes a lasting diastolic standstill of the frog heart beating in connec- 
tion with the frog-heart manometer, if the digitalis bodies have been added to the 
nutrient fluid in quantities distinctly smaller than those which, under like 
conditions, cause the systolic standstill {W&rsohinin). This standstill in diastole 
occurring after very small doses of digitalis is the maximal expression of the 
"diastolic" action of digitalis, while the systolic standstill is that of the 
"systolic" action. In the frog under the conditions of the normal circulation, 
the "'systolic" action always gains the upper hand when the dose is large 
enough to produce any effects. However, during the gradual absorption of small 
doses one may observe, in the intact frog or with a Williams apparatus, a 
contest between the two actions, during which fairly long diastolic pauses occur 
before the systolic stoppage takes place. 



264 



PHARMACOLOGY OF CIRCULATION 



The "diastolic" digitalis action — slowing of the heart rate and in- 
crease of the relaxation — resembles an inhibitory action, and the 
strengthening of the contractions reminds one of a stimulating action 
on the accelerator nerves, but they both occur quite independently of 
the extracardial nerves. It is not possible at the present time to 
determine which of the elements in the heart are acted on by the 
digitalis bodies. 

The action on the isolated mammalian heart is fundamentally 
similar to that on the frog's heart, except that in the mammalian 
heart the "diastolic" digitalis action is overshadowed by the systolic 
(Hedbom). The slowing of the pulse, which in man is well marked 
after medicinal doses, as also in the early stages of poisoning in the 
higher animals, is not caused peripherally, as is the case in the frog's 
heart, but is, at least in the case of most of the pure principles thus 
far investigated, entirely the result of stimulation of the vagus centre. 
It therefore does not occur after section of the vagi, or after destruc- 
tion of the central nervous system, or after atropine ( Acker mann, 
Kochmann) . 




Before digitoxin 



After digitoxi 



-Curves obtained from a surviving cat's heart. 



That "diastolic" action of digitalis which occurs independently 
of the vagus is only faintly indicated in the mammalian heart under 
the influence of this drug, although a more pronounced relaxation in 
diastole has been observed in the cat's heart when perfused with 
digitalis according to Langendorff's method. On the contrary, the 
pulse frequency of the mammalian heart is markedly increased when 
it is isolated and rendered independent of the central nervous system 
and subjected to the influence of digitalis. It may be that this pre- 
ponderance of the accelerator action is responsible for the fact that 
the ''diastolic" action of digitalis, which is so well developed in the 
frog's heart, is barely indicated in the mammal. 

In the isolated mammalian heart the "systolic" digitalis action 
causes a more complete contraction, in which evidently both ventricles 
are involved (Brawn u. Mayer). The effect of the more complete 
systole on the blood-pressure and on the pulse volume of the heart 
can be measured by inserting into the empty ventricle a balloon which 
just fills its cavity and which measures the changes in its pressure 
and volume. Under the influence of the digitalis bodies the work done 



DIGITALIS AND THE HEART 265 

by a single contraction of the heart can be augmented 2y 2 to 3 times 
(Gottlieb u. Magnus). 

As the poisoning develops these early effects are followed, just 
as is the case with the frog 's heart, by irregularity of the heart action, 
and finally, as the heart relaxes less and less, the heart stops in a state 
of maximal contraction. This systolic standstill of the mammalian 
heart may also at first be removed by forcible dilatation of the con- 
tracted muscle-fibres. 

The fact that the heart, beating in the intact circulation, finally stops in 
diastole instead of in systole is not due to a qualitative difference in the end 
stages of the toxic action in cold- and warm-blooded animals, but to the greater 
susceptibility of the mammalian heart to an interruption of its coronary circu- 
lation, the harmful effect of even moderate diminution of the diastolic relaxation 
so interfering with the blood supply of the heart muscles that, unless the heart 
be artificially perfused, the further development of the augmentation of the 
systolic contraction is interrupted. 



Strophanlhin blood 



Systolic standstill 




Fig. 28. — 1. Increase in the variations of the intraventricular pressure after strophanthin. 
2. Their progressive diminution until finally the heart stops in systole. 

Another fundamental action of digitalis, that of regulating a 
previously irregular cardiac action, is well brought out on the isolated 
mammalian heart. Even after small dosage this action is clearly 
developed and is therapeutically of great significance, but thus far this 
action is not susceptible of a closer analysis (see- p. 266). 

It may readily be understood that the improvement of the cardiac 
function by digitalis will be materially dependent on the character 
of contractions at the time when the drug is used. If before its 
administration the systolic contraction is already a nearly optimal 
one, the augmentation of the heart's performance will not be so great 
as it would be in case the contractions were feeble. This action may, 
therefore, be better demonstrated on a Langendorff 's heart prepara- 
tion which is relatively poorly supplied with blood, and which is 
beating relatively weakly, than on a fully normal organ, which is 
normally contracting nearly to its full extent in the circulation of a 
healthy animal (Magnus u. Sowton). Bock, in his experiments 
with the "heart-lung" circulation, found that the rise in blood- 
pressure resulting from an increase of the pulse volume of the heart 
was especially striking in hearts which had been beating inefficiently. 

An augmentation of the pulse volume of the heart beating in the 
intact, circulation must, under otherwise equal conditions, cause an 
increase of the aortic blood-pressure. In accord with this the mean 



266 PHARMACOLOGY OF CIRCULATION 

pressure in the Williams frog-heart apparatus is increased by the 
digitalis bodies (see curve, Fig. 26, p. 263). 

On the other hand, the pressure in the pulmonary arteries is not 
increased, or at least is much less increased than the pressure in the 
aorta. This difference is not due to a different action on the two 
ventricles, but to the fact that the pulmonary vessels are more readily 
distended and may be more easily filled without increasing the resist- 
ance in them (Wood, Openchowski, Mellin, Plumier). 

The volume changes of the ventricle may be measured in the 
living animal by means of the pletlrysmograph or similar instruments 
(Cushny), a diminution of the heart volume in systole justifying 
the conclusion that its contents are more completely expelled. The 
total amount of work done by the heart beating in the intact circu- 
lation depends, however, not alone on the pulse volume of the single 
heart-beats but on the pulse frequency. In the therapeutically im- 
portant stage of their action, the stimulation of the vagus centre 
by the digitalis bodies may so diminish the number of heart-beats 
that the minute volume of blood pumped out by the heart is, as a 
result of this slowing, increased only moderately, or may in fact 
be actually diminished. 

After toxic doses of digitalis a sudden change in the rate of the 
pulse, from retardation to acceleration, may occur. This is due to a 
peripheral vagus depression or, more correctly expressed, to an over- 
excitability of the heart that renders it less susceptible to vagus inhibi- 
tion. With large enough doses there finally develops irregularity of 
the heart action, and usually the heart stops very suddenly in diastole 
or in systole (see above). 

[To-day no discussion of the action of digitalis on the heart is com- 
plete unless it includes at least a brief consideration of its effects on 
the functions of conductivity and irritability or excitability (see 
p. 244). Largely through the admirable work of Mackenzie, augmented 
by the observations of Cushny, Lewis, and others, it appears to be 
established that in laboratory animals and in man under clinical 
conditions, digitalis and its congeners produce a distinct retarding 
effect on the conductivity of the Bundle of His, varying from a slight 
retardation to a complete blocking. As especially pointed out and 
emphasized by Mackenzie, this complete or partial blocking effect of 
digitalis may be of decisive importance for the therapeutic effect pro- 
duced, resulting at times to the advantage and at others to the 
disadvantage of the patient. Clinical observations, combined with 
subsequent post-mortem examination, have demonstrated that certain 
pathological changes in this Bundle of His favor the development 
of this blocking effect. 

In this connection it appears well to emphasize the clinical impor- 
tance of the action of digitalis in exciting or rendering more irritable 
the motor sranglia or centres in the heart, for it has been established 



CAFFEINE AND THE HEART 267 

clinically that under the influence of digitalis the tendency to pre- 
mature contractions or extra systoles may be decidedly aggravated. 
It should, however, be stated at the same time that, by its other actions 
on the whole circulatory system, the administration of digitalis may 
bring about a generally improved circulation, although increasing the 
tendency to extra systoles, or at times causing them to diminish in 
frequency or disappear at least for an indefinite period. — Te.] 

BIBLIOGRAPHY 

Ackermann: Deut. Arch. f. klin. Med., 1S73, vol. 11. 

Bock : Arch. f. exp. Path. u. Pharm., 1898, vol. 41. 

Bohm: Pfliiger's Arch., 1872, vol. 5. 

Braun u. Mayer: Sitzungsber. d. Akad. d. Wiss., Wien, 1899, vol. 108. 

Oushny: Am. Journ. of Exper. Med., 1897, vol. 2. 

Gottlieb u. Magnus: Arch. f. exp. Path. u. Pharm., 1903, vol. 51. 

Hedbom: Skand. Arch. f. Physiol., 1898, vol. 8. 

Kochmann: Arch, de Pharmacodyn. et de Therapie, 1905, vol. 16. 

Lhotak: Arch. f. exp. Path. u. Pharm., 1908, vol. 58. 

Magnus u. Sowton: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 255. 

Mellin: Skand. Arch. f. Physiol., 1904, p. 149. 

Openchowski : Ztschr. f. klin. Med., 1887, vol. 16. 

Plumier: Journal de Physiologie et Pathologie generale, 1905, vol. 7. 

Schmiedeberg : Beitr. zur Physiologie, Leipzig, 1875. 

Werschinin: Arch. f. exp. Path. u. Pharm., 1909, vol. 60. 

Williams: Arch. f. exp. Path. u. Pharm., 1880, vol. 13. 

Wood: Am. Journ. of Physiol., 1902, vol. 6. 

Caffeine. — To the discussion of the pharmacology of the digitalis 
group succeeds that of caffeine, which is often considered by clinicians 
to resemble digitalis. Its chief action on the circulation is, however, 
exerted upon the vasomotor centres, but it is necessary to make clear 
how the heart behaves under these conditions. If caffeine raises the 
blood-pressure, there necessarily results an improvement of the cardiac 
action, for, on account of the narrowing of the vessels, more blood 
flows back into the heart. 

In an isolated frog's heart, rendered independent of indirect in- 
fluence through changes in the blood-vessels, it is not possible to demon- 
strate that there is any increase in the work done against the normal 
resistance, and large doses quickly exert a harmful effect on the 
heart, while even after small doses the pulse volume of the frog's 
heart is not distinctly increased (Maki). On the other hand, even 
after small doses there is an augmentation of the "absolute power" 
of the heart, — that is, it is able to empty itself against a greater 
resistance than before (Dresrr 1 ). "We have here an action on the 
cardiac muscle analogous to the action of caffeine on voluntary 
muscles, the absolute power of which is also increased by caffeine 
(Dreser 2 ). 

Difference in Cardiac Action of Caffeine and of Digitalis. — In 
accordance with the above, the action of caffeine on the frog's heart 
is quite different from that of the digitalis bodies. In contradistinc- 
tion to those drugs, caffeine has do Pavorable "diastolic" action. On 



268 PHARMACOLOGY OF CIRCULATION 

the contrary, from the start it lessens the extent of relaxation and 
thus, especially in the mammalian heart, diminishes its pulse volume. 
This results from the fact that caffeine increases the tendency of the 
cardiac muscle to remain contracted, just as it does with voluntary 
muscles, and at the same time it hinders the relaxation of the heart 
in diastole. "While one may compare the heart under the influence 
of digitalis with a pump the piston of which makes greater excursions 
but is unable to overcome any greater maximal pressure, under the 
influence of caffeine the volume of blood forced out by single contrac- 
tions is at no time increased, but the heart can overcome a greater 
maximal blood-pressure. A favorable action on the heart could, there- 
fore, result, especially when there is an abnormally high resistance in 
the vessels. The observations of Bock on the "heart-lung" circulation 
of the rabbit are in accord with these conclusions. 

Although, on the other hand, Hedbom observed that in the mammalian heart, 
perfused according 1 to Langendorff, caffeine caused both an increase in the fre- 
quency and a distinct increase in the amplitude of the heart-beat, this may be 
explained by its specific power to dilate the coronary vessels. The improved blood 
supply thus obtained increases the strength of the contractions in the artificially 
perfused heart to such a degree that any diminution in the diastolic relaxation 
is compensated for. 

Caffeine accelerates the action of the isolated mammalian heart by 
a direct action in the heart. As this occurs after atropine and as the 
vagus nerve-ends remain excitable (Wagner) this pulse acceleration 
cannot be the result of a depression of the inhibitory mechanism, but 
is due to a stimulation of the cardiac accelerator mechanism.* 

The acceleration of the pulse after caffeine is well developed in the 
first stages only if the heart is beating independently of the control 
of the central nervous system. On the other hand, in the intact 
animal caffeine excites the vagus centre just as it does other nervous 
centres. With small doses this effect is the predominant one, so that 
usually at the start the pulse is retarded if the vagi are intact. In 
man also (Riegel. Kunkel) the pulse may be slowed by therapeutic 
doses of caffeine (0.2-0.5 gm.).f Only after larger doses does the 
acceleration of the pulse occur, this being a result of a direct action 
on the heart. 

After toxic doses, and also temporarily after the intravenous injec- 
tion of the small doses, in experiments on animals, the heart action 
becomes feeble and arhythmic, and finally fibrillation of the heart 
develops and the heart stops in diastole. 

BIBLIOGRAPHY 

Bock: Arch. f. exp. Path. u. Pharm., 1900, vol. 43. 
1 Dreser: Arch. f. exp. Path. u. Pharm., 1887, vol. 24. 
2 Dreser: Arch. f. exp. Path u. Pharm., 1890, vol. 27. 

* [Like digitalis caffeine also by its action on the intracardiac motor mechan- 
ism may cause or aggravate a tendency to premature contractions (extra 
systoles).— Tr.] 

f [In man the rule is that caffeine accelerates the pulse. — Tr,] 



FACTORS AFFECTING THE HEART 269 

Hedbom: Skand. Arch. f. Physiol., 1898, vol. 8. 

Johannson: Diss., Dorpat, 1869. 

Kunkel: Toxikologie, Jena, 1899, p. 576. 

MaM: Diss., Strassburg, 1884. 

Riegel: Verh. d. Kongr. f. inn. Med., Wiesbaden, 1884. 

Wagner: Diss., Berlin, 1885. 

Other Factors Affecting the Heart Action. — From experi- 
ments on the surviving mammalian heart, it is known that its excita- 
bility and capacity for work depend to a great degree on the tem- 
perature and on special chemical conditions, — that is, on the correct 
composition of the perfusing fluid. A considerable rapidity in the 
flow of the nutrient solution is also necessary for the maintenance of 
the normal chemical processes in the mammalian heart, for it would 
appear that the demand for oxygen made by the actively beating heart 
necessitates this rapid flow. On the other hand, a heart may beat 
for hours in a hamioglobin-free fluid or in blood rich in carbon mon- 
oxide (Strecker), the small quantities of oxygen absorbed by the salt 
solution being sufficient to maintain this function. However, the 
power of the contractions of the mammalian heart and its capacity 
for work are dependent in a high degree upon the supply of oxygen, 
just as is the case with every muscle {Bolide). 

A rapid flow through the vessels of the heart is also necessary 
to remove or to neutralize those metabolic products, resulting from 
the cardiac activity, which exert a depressant action on the heart. 
Such a substance is, for example, carbon dioxide, the accumulation 
of which in the heart inhibits its activity. 

For the maintenance of the chemical equilibrium in the heart, we 
need a nutrient medium adjusted properly to this equilibrium. Each 
smallest alteration in the proportions of the chemical constituents of 
the nutrient solution — for example, the loss or removal of any of 
them, especially the loss or diminution of the calcium salts — causes 
severe disturbances, just as in all other susceptible organs. Especially 
in the heart these disturbances are quickly and clearly manifested by 
changes in its automatic activity. 

Physiological sodium chloride solution alone is not capable of 
maintaining the function of the heart for any considerable period, the 
heart becoming exhausted and being harmfully effected by it, so that 
its excitability and functional powers gradually fail (Martins). The 
heart function is maintained far better by a solution containing all 
the salts normally present in the blood, — e.g., those of the blood ash 
(Mrrunowitsch). As solutions which besides NaCl and a calcium 
salt also contain Na.CO., or NaOH act more favorably, the significance 
of the alkaline salts of the blood may be sought also in their power 
of neutralizing acid metabolic products (Gothlin). According to 
all more recent investigations, calcium appears especially important. 
Ringer was the first to show that, In addition to common salt, CaCl and 
KC1 must be present in the nutrient solution in order to obtain the 



270 PHARMACOLOGY OF CIRCULATION 

best possible performance by the heart. An improvement in the 
function of cold- and warm-blooded hearts results from the addition 
of calcium to a solution containing enough NaCl to maintain the 
proper osmotic pressure. Such addition causes increased and more 
energetic contractions, but gradually the relaxation becomes incom- 
plete and the heart-beats thus become less efficient (Langendorff). 
Potassium, on the other hand, if added by itself to the NaCl solution, 
favors relaxation and ultimately causes a diastolic standstill. Calcium 
and potassium are thus seen to work antagonistically to each other and, 
when both are present, to compensate each other. In the proportions 
used in Ringer's solution the calcium preponderates. Under the con- 
ditions obtaining in the blood in which both of these ions are present, 
we are, therefore, dealing with a compensated calcium action (Ringer, 
Gross). 

BIBLIOGRAPHY 
Gothlin: Skand. Arch. f. Physiol,, 1901, vol. 12. 
Gross: Pfliiger's Arch., 1903, vol. 99. 
Kronecker: Festschrift f. C. Ludwig, Leipzig, 1875. 
Langendorff u. Hueck: Pfliiger's Arch., 1903, vol. 96. 
Martius: Du Bois' Arch. f. Physiol., 1882. 
Merunowitsch : Ludwig's Arbeiten, 1870, vol. 10. 
Ringer: Journ. of Phvsiol.. 1887. vol. S. 
Rohde: Ztschr. f. phvsiol. Chemie, 1910, vol. 86, p. 181. 
Straub: Arch. f. exp. Path. u. Pharm., 1901, vol. 45. 
Strecker: Pfliiger's Arch., 1900, vol. 80. 

PHARMACOLOGICAL ACTION OX THE VESSELS 
Like the heart, the vessels have a double innervation through the 
vasoconstrictors and vasodilators, their interplay maintaining the com- 
pensatory regulations in the circulation by which the blood supply of 
the vital organs is preserved (see page 231 ff.). With the assist- 
ance of the vasomotor centres, the regulative constriction of other 
vascular systems is brought about when any vascular system is dilated, 
and in the same fashion vasoconstriction of one system is compensated 
for by vasodilatation in others, so that the blood supply of the organs 
can vary within large limits, according to their changing needs, 
without any alteration in the general blood-pressure. In numerous 
pharmacological actions a similar mechanism is called into play, so 
that under their influence only the distribution of the blood is 
altered, the pressure in the aorta remaining constant. 

Probably the vasoconstrictors as well as the vasodilators control 
these compensations in the vascular system. Their cooperation would 
appear to be secured by means of a reciprocal intracentral inhibition, 
so that, for example, decreased tonus of the vasoconstrictor centres 
automatically results in a stimulation of the vasodilator centres. The 
two mechanisms thus normally never act in opposition, but always 
together. 

As a result of this double innervation any change in vessel calibre 
— for example, relaxation in a particular vascular system — may occur 



PHARMACOLOGY OF THE VESSELS 271 

in two ways, — either by depression of the vasoconstrictors or by stimu- 
lation of the vasodilators. Both of these effects may be due to an 
action on the centres or on the peripheral mechanism. 

There are also in the vessel walls peripheral vasomotor nerve- 
ganglia, pharmacological action on which cannot be differentiated 
from that on the terminal mechanisms. The existence of these periph- 
eral vasomotor nerve-ganglia is proved by the fact that, even after 
separation from the central nervous system, — for example, after 
section of the vasomotor nerves, — certain vascular systems do not 
remain maximally dilated but gradually regain their power to react. 
The significance of this peripheral vascular tonus is best demonstrated 
in the experiments of Eicald and Goltz, in which, after destruction 
of the dorsal and sacral cord and section of the sciatic of the dog, 
there developed in the lower extremities a vascular tonus independent 
of all central influence. The intestinal vessels also, after section of 
the splanchnics, gradually regained their tonus with the assistance 
of peripheral mechanisms, and the blood-pressure was re-established. 

Finally, alterations of vessel calibre depend, in the last instance, 
on the muscles in the arterial walls. An example of a probably 
direct action on these muscles may be seen in the vasoconstriction 
produced by barium salts. However, it is hardly possible to differ- 
entiate with certainty between a pharmacological action on nerve- 
endings in the vessel wall and that on their muscles. 

All these changes in the calibre of the vessels may affect only one 
vascular system or many at one time. In such case, the central action 
on the vessel innervation and the peripheral changes in the vessel wall 
produced by one and the same drug may cause similar or opposite 
effects, so that, for example, vasodilatation in the kidney, due to a 
peripheral action, may occur at the same time with vasoconstriction 
in other situations, this latter being the result of a central action. It 
is thus comprehensible that the distribution of the blood may be 
affected by drugs in the most manifold fashion. 

That under these conditions the aortic pressure remains un- 
changed is due to the already discussed compensating mechanism of 
the circulation, the behavior of the vessels of the intestine, the liver, 
and the spleen being of decisive importance for this power of accom- 
modation. On account of its great capacity, the portal system is able 
to furnish enough blood for the filling of the other vascular systems, 
or, on title other hand, as a result of its great distensibility, it is able 
to accommodate blood forced out from other parts of the body, thus 
compensating for vasoconstriction elsewhere. 

Only by the investigation in detail of the different vascular sys- 
tems — for example, by means of plethysmography — is it possible to 
recognize these variations in the distribution of the blood, as long as 
in their early stages their effect on the aortic pressure is compensated 



272 PHARMACOLOGY OF CIRCULATION 

for by the compensatory behavior of the different vascular systems. 
Only very pronounced vasomotor effects cause changes in the aortic 
pressure. 

By stimulation of the splanchnic Mall was able to transfer 27 per cent, 
of the total blood contents of a dog from the portal circulation into other 
systems, the splanchnic stimulation causing constriction not only of the arteries 
but also of the veins in the portal system (Schmid). 

The splanchnic acts as the chief regulator of this compensating 
function. For this reason the blood-pressure in the aorta remains 
normal, even if, for example, the vessels of the skin be ever so 
extremely dilated by antipyrine. However, the total cross-section 
of the arterial tree may be maintained constant only as long as the 
portal system remains under the control of its vasomotor inner- 
vation, for any marked dilatation of the hepatic and intestinal vessels 
cannot be compensated for, and, therefore, if vasomotor depressants, 
such as certain bacterial toxins, act on the centres controlling the 
visceral vessels, this compensation does not occur and the aortic 
pressure sinks. 

Constriction of the visceral vessels mechanically and reflexly forces the 
blood into other vascular systems. If, for example, the vessels of the skin and 
muscles are dilated while simultaneously the splanchnic vessels are constricted, 
it may be a question whether this be due to a direct action in dilated systems 
or to expulsion of the blood from the visceral vessels into those of the skin and 
muscles. This point must be especially remembered in considering the early 
stages of the action of alcohol and ether, as also in connection with the dilatation 
of the cutaneous vessels in atropine poisoning. 

In the different species the relative importance quantitatively of the different 
vascular systems can vary greatly. In particular, it is difficult to compare the 
cutaneous vessels of man with those of the animals used in our experiments, for 
in man the skin, as an important organ for the loss of heat, plays a quite 
different role from that played by the hide of these animals, and accordingly 
in man the cutaneous vessels are much more numerous and more subject to 
nervous influences. Moreover, the different relative size of the extremities and 
the trunk in man and in the small laboratory animals is a further factor to be 
considered. On the other hand, the length of the alimentary canal has an effect 
on the influence exerted by the splanchnic vessls on the distribution of the blood. 
For this reason, after section of the splanchnic, the blood-pressure does not fall 
as much in the dog as in the rabbit. 

As a result of the above-described compensatory mechanism in the 
circulation, we may expect only an alteration in the distribution of 
the blood, without change in the general blood-pressure, to result 
from the moderate vasomotor effects of drugs. Only if a pharmaco- 
logical action overcomes this regulation will the circulatory condition 
in the whole body be affected and the carotid pressure be changed. 

BIBLIOGRAPHY 

Mall: Dubois' Arch., 1892, p. 409. 

Schmid: Habilitationsschrift, Breslau, 1907. 

Schmid: Pfliiger's Arch., 1909, vol. 126, p. 165. 



CENTRAL VASOCONSTRICTORS 



273 



CENTRALLY ACTING VASOCOXSTRICTING DRUGS 
Strychnine. — The excitability of the vasoconstrictor centres is 
augmented by strychnine in the same way in which the spinal reflexes 
controlling motor functions are rendered over-excitable by this drug. 
With the maximal development of the strychnine action, therefore, a 
tetanus of the muscles of the vessel walls occurs simultaneously with 
the outbreak of the tetanus of the striped muscles, and thus the aortic 
pressure is tremendously raised. This vascular cramp is, however, 
independent of the tonic contractions of the voluntary muscles for 
it occurs in the curarized animal (see Fig. 29). The vagus centre is 
also stimulated simultaneously with the vasomotor centres (8. Mayer). 




IVyi/WM 




J 11 I I I I 1 I I I I 1 I I M 1 1 1 I I I I I I I t I 1 I 1 I t M M II I I I I I 

Strychnine nitr. 0.6 mg. p. Kilo 

Fig. 29. — The effect of strychnine on the blood-pressure of a curarized cat. 

After division of the cord in the neck, strychnine raises the blood-pressure 
to a much slighter extent, but some rise does occur, especially in young animals, 
so that, after isolating the vascular system from the main centres in the medulla, 
Btrychnine may be used to demonstrate the existence of accessory vasomotor 
centres in the spinal cord (Schlesinger) . On the heart, strychnine exerts a 
depressing influence only in doses which are much larger than those causing 
convulsions (Igersheimer). 



All of the vascular systems are by no means equally affected 
by strychnine. On the contrary, practically only the vessels in the 
portal system are constricted, as may be shown by the simple inspection 
of the exposed intestines. Plethysmographically, diminution in their 
volume — for example, in the kidney — may be demonstrated while the 
peripheral vessels may be shown to be dilated (Wcrthcimer et Dele- 
zcnnc) . 
18 



274 PHARMACOLOGY OF CIRCULATION 

BIBLIOGRAPHY 

Igersheimer: Arch. f. exp. Path. u. Pharm., 1905, vol. 54, p. 73. 
Mayer, S.: Wien. sitzungsbericht d. Akad., 1871, vol. 54, part 2. 
Schlesinger: Wien. med. Jahrbuch, 1873. 
Wertheimer et Delezenne: Compt. rend, de la Soc. de Biol., 1897, p. 633. 

Caffeine's action on the vasomotor centres is analogous to that 
of strychnine, just as large doses of caffeine cause convulsions. How- 
ever, the stimulation of the vasomotor centres by caffeine does not 
result in as marked a rise in pressure, because the action of the 
caffeine on these centres is complicated by the influence exerted at 
the same time on the frequency of the pulse and on the pulse volume 
of the heart. In animals it may be demonstrated that especially 
medium-sized doses cause an increase in blood-pressure, while still 
larger doses produce no change in the blood-pressure. Very large 
doses, as well as very rapid direct injection of the drug into the 
veins, cause a fall in pressure, resulting from the depression of the 
functional power of the heart, which is undoubtedly caused by the 
strong concentration of caffeine acting directly on the heart (see 
p. 268). 

Besides acting on the vasomotor centres, caffeine acts also on the 
vessels in the periphery. This action on the vessel walls is, however, 
the opposite of its central action, for by its peripheral action it dilates 
the vessels of the heart, kidney, and brain. The two dimethylxan- 
thines, theobromine and theophylline, also possess this peripheral 
vasodilator action (see p. 330), while their action on the vasoconstrictor 
centres is much less pronounced, although they, in their chemical 
nature and pharmacological action, closely resemble caffeine. 

Camphor, picrotoxin, and other medullary convulsants also 
stimulate the vasoconstrictor centres. Doses large enough to cause 
convulsions raise the blood-pressure, for the constriction of the 
visceral vessels overcomes the regulatory mechanism which ordinarily 
prevents any alteration of the general pressure (Wiedemann). In 
such case the blood distribution is similar to that resulting from the 
action of strychnine and caffeine. It is probable that camphor can 
exert a favorable action on depressed vasomotor centres, for in experi- 
ments on chloralized animals these centres, which had become insus- 
ceptible to stimulation by asphyxia or by sensory reflexes, again 
became excitable (Alexander-Leivin). Simultaneously with the vaso- 
constriction in the interior of the body, the cutaneous vessels are 
dilated. 

BIBLIOGRAPHY 

Alexander-Lewin : Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 226. 
Wiedemann: Arch. f. exp. Path. u. Pharm., 1876, vol. 6, p. 216. 

Alcohol affects the calibre of the vessels in different organs in a 
very manifold fashion. The cutaneous vessels are dilated even by 
small doses, while in the first phases of its action the visceral vessels 



CENTRAL VASOCONSTRICTORS 275 

appear to be constricted. It is probable that the dilatation of the 
cutaneous vessels is only partly the result of the constriction of the 
visceral vessels. Like many other pharmacologically closely related 
substances, alcohol possesses the power of slightly lessening the central 
vasoconstrictor tonus for the cutaneous vessels, but the accompanying 
constriction of the visceral vessels, which is produced by small doses 
of alcohol, is in part due to a peripheral action, and, according to 
Dixon, also in part a result of central action. In consequence of these 
opposite effects on the different vascular systems, a change in the 
blood distribution but no important change in the blood-pressure may 
be expected to result from small doses of alcohol ; but after intravenous 
injection of appropriate doses the vasoconstriction in the splanchnic 
system may be pronounced enough to raise the pressure in the carotid 
(Dixon, Haskovec, Koclimann), while with still larger doses alcohol 
dilates not only the cutaneous vessels but also all the others, and, as 
the splanchnic vessels are affected with the others, the blood-pressure 
falls. 

BIBLIOGRAPHY 

Dixon: Journ. of Physiol., 1907, vol. 35, p. 346. 

Haskovec: Arch, de medecine experim., 1901, vol. 13, p. 539. 

Kochmann: Arch, intern, de Pharmacodyn., 1904, vol. 13, p. 329. 

Ether. — According to Derouaux, ether similarly affects the dis- 
tribution of the blood. In the dog a slight rise in blood-pressure is 
observed after subcutaneous injection, but this is much more marked 
after the intravenous injection of a properly chosen dose. As shown 
by the plethysmography curves, the visceral vessels are constricted and 
those in the periphery dilated during the period of increased blood- 
pressure. The early rise in blood-pressure during narcosis and the 
improvement of the heart action following hypodermic injections of 
ether (see p. 257) are to be explained as reflex actions caused by the 
irritation produced by the ether in the mucous membranes or at the 
point of injection. [This conclusion, that this is the sole cause of the 
rise in blood-pressure observed in narcosis, appears to the translator 
not justified either by the clinical or the experimental evidence.] 

BIBLIOGRAPHY 
Derouaux: Arch, intern, de Pharmacodyn. et de Therap., 1909, vol. 19, p. 63. 

The behavior of the cutaneous and visceral vessels during the early 
stages of the action of alcohol and ether is a good example of the 
quantitative differences in the reaction of the different vasomotor 
centres to identical pharmacological influences. The cutaneous ves- 
sels react readily to the dilating action of the narcotics, but the 
splanchnic vessels only after much larger doses. This especial sus- 
ceptibility of the cutaneous vessels to the dilating action of centrally 
depressing drugs is best developed in the vessels of the face. The 



276 PHARMACOLOGY OF CIRCULATION 

other cutaneous vessels are dilated only after larger dosage, while 
the vessels in other parts of the body are the last to be affected. 
Of such causation is the flushing of the face during ether narcosis or 
at the start of chloroform narcosis and that caused by the drinking 
of wines with strong bouquet, as well as by morphine in certain indi- 
viduals. It is most strongly expressed during the action of amyl 
nitrite. 

The antipyretics and atropine cause redness of the skin in an 
especially elective fashion, no other vessels being dilated even by 
quite large doses. One might be tempted to attribute this action of 
the antipyretics to depression of the vasoconstrictor centres, and in 
the case of atropine, with its power of acting as a general central 
stimulant, to stimulation of the vasodilator centres. It is not possible, 
however, to decide positively between these two possible seats of action. 
Perhaps both mechanisms are simultaneously influenced by these drugs 
but in different directions, just as physiologically these centres ordi- 
narily compensate each other as a result of their antagonistic 
actions. 

CENTRALLY ACTING VASODILATING DRUGS 

Narcotics. — In large doses narcotics of the alcohol group, espe- 
cially chloroform or chloral hydrate, and also numerous alkaloids, — 
e.g., morphine in toxic doses, — cause a gradual diminution in the 
excitability and finally a general paralysis of the vasomotor centres, 
the pulse becoming soft and the blood-pressure gradually falling. 
The same is true of numerous other central depressants and especially 
of bacterial toxins, — for example, diphtheria toxin. 

Amyl nitrite is the most powerful of these vasodilating drugs, 
the inhalation of the fumes of 2-5 drops causing almost instantaneous 
flushing and a feeling of warmth of the face, pulsation of the carotids, 
and acceleration of the heart-beats. At the same time the head 
swims and a feeling of slight drunkenness develops. The brilliant 
redness of the skin extends from the face over the throat and chest, 
but rarely extends below the waist. After a few minutes the effects 
of small doses pass off. 

The temperature of the profusely reddened skin is raised, thermo- 
electric measurements indicating a rise in temperature of the skin of 
as much as 3° C. (Amtz, Lahnstein) . 

In man it has been demonstrated that the vasodilatation produced 
by small doses is confined to the skin of the head and trunk and to 
the vessels of the brain, while probably the coronary vessels are also 
affected even by small doses. The dilatation may be particularly 
well demonstrated in the rabbit's ear, especially in tracheotomized 
subjects, as by this means it is possible to exclude the disturbing re- 
flexes due to the action of the irritating vapor on the nasal mucous 
membrane. The participation of the cerebral vessels may be proved 
by inspection of the pia mater of trepanned animals, or by measuring 



CENTRAL VASODILATORS 277 

the blood flowing out of the cerebral veins ( Gartner u. Wagner, Schiil- 
ler, Schramm, Hiirthle). Mo&so was able to observe an increase 
in the volume of the brain in a case with a cranial defect. Plethys- 
mographic curves were taken at the same time from the forearm and 
foot, and it was found that vasodilatation in the forearm occurred 
somewhat later than the increase of blood flow to the brain, while 
during the action of the drug the volume of the foot was constantly 
diminished below the normal. 

The radial pulse is larger and softer during the action of amyl 
nitrite, its rate rising, after a few inhalations, approximately from 
75 to 98 in the minute. Animal experiments similarly show a fall 
in blood-pressure and acceleration of the pulse. 

That the vasodilatation is due primarily to an action on the 
centres was proved by the experiments of Filehne, who caused rabbits 
to inhale amyl nitrite, the blood circulation in the brain and medulla 
being part of the time maintained and part of the time interrupted 
by clamping the internal carotids and the subclavian arteries. The 
vasodilatation in the rabbit's ear did not occur when the circulation 
of the brain was interrupted, although the blood flowing through these 
vessels contained the drug. In other experiments in which the circu- 
lation through the centres was intact and in which the drug reached 
them, the vessels of the ear dilated even when these vessels were sup- 
plied with blood containing none of the drug. 

In large quantities, however (quite independently of its action 
on the centres), amyl nitrite depresses the tone of the vessels by a 
peripheral action. This peripheral vasodilating action of amyl nitrite 
is perhaps of considerable therapeutic significance. That such periph- 
eral action occurs is proved by the fact that the blood-pressure falls 
during inhalation of the drug, even when, by previous section of the 
cervical cord or by ligation of all arteries supplying the brain, the 
principal vasomotor centres have been eliminated (Lauder-Brunton, 1 
S. Mayer u. Friedrich). 

That in this case the action takes place in the vessel wall and not in the 
subsidiary centres in the cord is indicated by the results of perfusion of isolated 
organs, as also by the fact that injection of a nitrite into the carotid causes at 
first dilatation of the vessels of the brain alone (Biedl u. Reiner). 

in toxic doses the blood-pressure is markedly lowered, and the rapid pulse 
becomes weak, but this is not due to an impairment of the heart's function, 
for the isolated heart is depressed only by still larger doses (Bock et al.). The 
fall in pressure and the enfeeblement of the pulse after toxic doses are, therefore, 
only the results of a general vasoparesis. 

As after section of the cervical vagi the increased frequency of the 
heart action does not occur, it is clear that the acceleration of the 
pulse is also an indirect effect due to the depression of the cardio- 
inhibitory centre, this resulting automatically from the fall in blood- 
pressure, for in Filehnc's experiments the acceleration of the pnlse 
disappeared if the blood-pressure was restored to the normal by tem- 
porary clamping of the abdominal aorta. 



278 PHARMACOLOGY OF CIRCULATION 

When the cardiac nerves are intact, it is a general rule that the frequency 
of the pulse increases with the fall in the general blood-pressure. The importance 
of this regulatory mechanism may be especially well demonstrated with amyl 
nitrite if its effects on the blood-pressure in the dog and rabbit be compared. 
In the dog the blood-pressure is only moderately lowered by this drug, because, 
simultaneously with the vasodilatation, the pulse becomes much more rapid. In 
the rabbit, on the other hand, as its vagus tone from the beginning is weak, 
the pulse-rate is much less increased, and the blood-pressure, therefore, markedly 
falls (Lauder-Brunton 3 ). In man, even after small doses the pulse is markedly 
accelerated. 

Toxic effects result from the continued inhalation of amyl nitrite, while 
nausea and vomiting are sometimes observed even after small doses. Such grave 
symptoms as fainting and collapse after large doses are due to the general 
vasoparesis. Grave poisoning has been seldom observed in man, as the effects 
resulting from the inhalation pass off very rapidly, and as amyl nitrite is only 
slowly absorbed from the stomach, so that 3 gm., in fact even 12 gm., taken by 
mouth have not caused fatal poisoning (Rosen). In animal experiments long- 
continued administration of large amounts of amyl nitrite causes convulsions, 
as well as a transformation of haemoglobinse into methamioglobin, an action 
which is characteristic of all nitrites (Gamgce, Giacosa). 

This action on the vessels is a nitrite action, although other amyl 
ethers dilate the vessels, — for example, amyl chloride, which, accord- 
ing to Hay, may be used for the same indications as amyl nitrite. 
Ethyl alcohol and other narcotics of this group also possess a similar 
action. However, the vasodilatation resulting from very small doses, 
which is characteristic of amyl nitrite, as well as the formation of 
metha?moglobin after large doses, is dependent on the nitrite radical, 
for the salts of nitrous acids, such as sodium nitrite, produce the same 
pronounced effect on the vascular systems. 

BIBLIOGRAPHY 

Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 158. 
Biedl u. Reiner: Plliiger's Arch., 1900, vol. 79, p. 158. 
Pilehne: Dubois' Arch. f. Physiol., 1879, p. 386. 
Filehne: Pfluger's Arch., 1874, vol. 9, p. 470. 
Giirtner u. Wagner: Wiener med. Woch., 1887. 
Gamgee: Transact. Royal Soc, Edinburgh, 1868. 
Giacosa: Ztschr. f. physiol. Cheinie, 1879, vol. 3, p. 54. 
Hay: The Practitioner, 1883. 
Hurthle: Pfliiger's Arch., 1889, vol. 44, p. 561. 
Lahnstein: Diss. Wiirzburg. 1S86. 

1 Lauder-Brunton : Ber. d. Kgl. Sachsischen Ges. d. Wiss., 1869, vol. 21, p. 285. 

2 Lauder-Brunton : Jour, of Anat. and Phys., 1870. 

Mayer, S., u. Friedrich: Arch. f. exp. Path. u. Pharm., 1875, vol. 5, p. 55. 
Mosso: Der Kreislauf d. Blutes in menschl. Gehirn, Leipzig, 1881 ; Die Temperatur 

des Gehirns, Leipzig, 1894. 
Rosen: Zbl. f. inn. Med., vol. 9, p. 777. 
Schiiller: Berl. klin. Woch.. 1874. 
Schramm: Diss., Strassburg, 1874. 

PERIPHERALLY ACTING VASOCONSTRICTORS 
Pharmacological action in the vessel walls may be due to an action 
on the nervous elements in the vessel wall or to an action on the con- 
tractile substance. However, we possess no methods which enable us 



PERIPHERAL VASOCONSTRICTORS 279 

to differentiate between these two possible seats of action in periph- 
eral vasoconstriction or dilatation. 

Epinephrin, cocaine, and the digitalis bodies stimulate the tone of 
all vessel walls [pulmonary and coronary vessels? — Tr.] In 1895 
Olive?' and Schaefer, and at the same time Gzybulshi and Szymonovicz, 
discovered that intravenous injections of extracts of the suprarenal 
glands caused an enormous rise in the blood-pressure. 

Epixephrix. — Immediately after this Moore demonstrated that the active 
substance was present only in the medullary portion of the glands, and that it 
was identical with a chromogenic substance, described by Tulpian as early as 
1856, possessing striking color reactions, — green coloration with iron chloride 
on the addition of alkalies, or with iodine or chlorine water a pink-carmine color. 
These reactions suggested brenzcatechin, and v. Fiirth succeeded in preparing 
from this chromogen, a substance which in its behavior agreed with brenz- 
catechin. The crystallized active substance was first prepared in 1901 by 
Takamine and named by him adrenaline. Other authors have given it the names 
of suprarenin, paranephrin, epinephrin, epirenan, etc. [As the council of 
Pharmacy and Chemistry of the A.M.A. has recommended " epinephrin " as the 
preferable name, this name will be used throughout this translation.] This 
substance, having the empiric formula C 9 H 13 N0 3 , is a base which is soluble in 
water and readily decomposes in alkaline solution, the solutions, like those of 
brenzcatechin, turning first red and then brown when exposed to the action of 
light. 

The constitution of epinephrin has been determined as that of a brenzcate- 
chin derivative of relative simple structure. It is an aminoalcohol (OH)oC 6 H s 
CH UH CH S XH CH 3 



ho / \ ch oh ch 2 nh ch 3 
ho' 



which may be prepared by reduction of methylaminoacetobrenzcatechin. 

Stoltz and Dalcin have succeeded in synthetically preparing epinephrin and 
a series of related brenzcatechin derivatives, which, according to Loeici and Hans 
Meyer, possess an action fully analogous to that of the natural alkaloid. This 
synthetic preparation may be obtained under the name of suprareninum syn- 
theticum. 

The natural alkaloid is laworotatory. The synthetically prepared 1-epi- 
nephrin is equally as active as this, while the action of r-epinephrin is 12-15 
times weaker. Recently A. Frbhlich found that very large doses of the dextro- 
rotatory alkaloid so affected the circulation that even one or more milligrammes 
of the laworotatory epinephrin produced no effect on the blood-pressure. 

The rise in blood-pressure is caused by the extreme constriction 
of the smallest arteries due to direct action on the vessel walls. Sec- 
ondarily, a direct and unusually powerful stimulating effect on the 
In ;nt, which has already been discussed, plays a role in the pro- 
duction of this rise. The proof that the vasoconstriction is due to 
peripheral action is furnished by experiments in which the rise in 
blood-pressure occurred after the cervical cord had been severed 
and the spinal cord pithed, or after complete elimination of the vaso- 
motor centres by means (it* chloral (Velich, Gottlieb' 1 ). Similarly, 
constriction of the separate vascular systems occurs after these are 
rendered independent of the vasomotor centres by section of their 
nerves (Fr. Pick, Loewi and II. Meyer). In artificial perfusion 



280 PHARMACOLOGY OF CIRCULATION 

of surviving organs the peripheral action on the vessels is expressed 
by retardation or even by a complete stoppage of the flow, which 
may occur even after maximal dilatation (Gottlieb 2 ). The direct 
action on the tone of the arterial walls may be shown in an especially 
instructive manner by experiments on isolated circular strips of the 
arteries. By the use of Ringer's solution kept at body temperature, 
these may survive for days and maintain their irritability, so that 
changes in their tone may be graphically recorded (If. v. Frey, 0. B. 
Meyer). After addition of epinephrin to the Ringer's solution, a 
distinct shortening of the strip of artery results. 

This vasoconstriction is especially well marked in the arteries 
of the splanchnic system, but occurs also in most of the other vascular 
systems (Cow). According to Langendorff, the coronary vessels are 
exceptional in their behavior, in that in them epinephrin, instead of 
causing an increase in the tone, causes a diminution, as shown by the 
lengthening of the strip. In accordance with this, the flow of the blood 
through the tissues of the surviving mammalian heart is not hindered 
but, on the contrary, is favored by epinephrin. 

Hcemo stasis,. — The use of epinephrin as a means of causing local 
anaemia and as a haemostatic depends on its power to constrict the 
vessels lying at the point of application. If the drug be applied 
(1-1000 or 1-10,000), in dilute solution, to mucous membranes or 
wounds, these become extremely pale. The anaemia resulting from its 
application greatly increases the accessibility of cavities lined by 
mucous membrane (for example, in rhinological practice) . In surgery, 
when it is important to have the operative field as free from blood as 
possible, epinephrin may be used locally to check hemorrhage. 

In Local Anaesthesia. — Mention has already been made of the great 
advantage resulting from the addition of this drug to the cocaine 
solutions employed in the induction of local anaesthesia. It is of great 
practical importance that the vasoconstriction caused by epinephrin 
closes up the paths for the absorption of the cocaine, and thus keeps 
this drug at the place of its application and does not permit it to 
reach the central nervous system (see p. 125). As shown by 
Meltzer and Auer and also by Exner, epinephrin delays absorption 
from the peritoneal cavity. It is also probable that the absorption 
through the lymph-spaces is hindered by its actions. 

Effects on Distribution of the Blood. — When epinephrin is injected 
directly into the circulation, the visceral vessels are especially con- 
stricted. Plethysmographic investigation shows a marked diminution 
in the volume of the intestines, kidney, and spleen, so that, in spite of 
the tremendous rise in blood-pressure, the curves from these organs 
move in an opposite direction from the blood-pressure curves (Fig. 
30). The blood is forced out of the abdominal viscera into the heart 
and lungs, the vessels of which are much less affected than those of the 
other organs fGerhardt). 



EPINEPHRIN 281 

The effects, on the blood-pressure may be obtained in their full 
development by the intravenous injection of a dose corresponding to 
1/100 mg. per kilo. "With subcutaneous injections doses more than 
one hundred times as large are necessary. [The translator has found 
that from 0.6 to 1.0 mg. injected intramuscularly usually caused dis- 
tinct effects in adult human beings, such as a rise of from 10 to 15 mm. 
Hg and an acceleration of the pulse, with apparent increase in the 
strength of the cardiac contractions. In two patients (out of a series 
of 30 cases) such doses caused tremendous pressor and other effects, 
the symptoms in one case being very alarming. The unusual effects 
were apparently due to individual idiosyncrasy, for these two cases 
reacted proportionately to smaller doses given subsequently. The 
translator knows of no adequate explanation for the difference in reac- 
tion to this drug which the laboratory animals and man present, but 
believes it important to warn against possible harm which might 
result from disregarding it.] 




— Left front 
leg 



Fig. 30. — Effect produced by suprarenal extracts on the blood-pressure and on the volume of 
different organs (Oliver and Schaefer). 

Causes of the Evanescence of the Pressor Effect. — The rise in 
blood-pressure following intravenous administration seldom lasts more 
than 1-3 minutes. This difference between the striking effects pro- 
duced by intravenous injection and the comparatively slight effects 
of subcutaneous injections is doubtless in part due to the great insta- 
bility of this drug, which is decomposed even by weak soda solutions. 
[Further, the local vasoconstriction must permit only a gradual en- 
trance of the drug in the general circulation. This would result in a 
lessened intensity and a greater persistence of the effects of the drug 
when administered subcutaneously (Miller, Halscy). — Tr.] The 
rapidity with which the effects of the intravenous injections pass off 
may be assumed to be due in part to a rapid oxidation of epinephrin 
in the alkaline medium of the body fluids and tissues. In addition 
it is assumed that this drug acts only at the moment of entrance into 
the nerve-endings [f] by a "permeation pressure." If this assump- 



282 PHARMACOLOGY OF CIRCULATION 

tion is correct, the manner in which epinephrin produces its effects 
would be analogous to that in which muscarine (p. 248) acts (Straub). 

Elimination. — Even when large amounts of epinephrin are ad- 
ministered subcutaneously or administered by mouth, only minimal 
amounts are excreted in the urine (v. Fiirth). 

Other Actions. — Epinephrin possesses a number of other pharma- 
cological actions in addition to this effect on the vessels, which is, 
for practical purposes, its most important action. One of these is 
the acceleration and strengthening of the heart-beat, as a result of 
stimulation of the accelerator nerves. The slowing of the pulse 
observed at the commencement of the rise in blood-pressure is the 
result of stimulation of the vagus centre by the increased blood- 
pressure (see p. 245) . The respiration during the period of high blood- 
pressure is affected in a peculiar manner, temporary cessation alter- 
nating with periods of deeper and more rapid breathing. 

Epinephrin causes mydriasis by stimulation of the dilator pupillae, analogous 
to that caused by stimulation of the sympathetic in the neck (p. 159). It causes 
increased secretion of the salivary glands (Langley) , as also of the glands of the 
skin of the frog {Ehrmann), and atropine does not stop these secretions when 
thus excited. Further, epinephrin, even in small doses, is a powerful excitant of 
the contractions of the uterus (pp. 222, 229), but, on the other hand, intestinal 
peristalsis is inhibited by it (p. 173). The epinephrin glycosuria (Blum, Herter 
and Wakeman) results from the stimulating effect on the transformation of gly- 
cogen in the liver. Glycosuria produced by brain puncture and many toxic gly- 
cosurias are to be considered as resulting from a suddenly increased secretion of 
epinephrin (p. 419). 

It is probable that the arteriosclerotic changes found in the aorta of animals 
which have for some time been treated with epinephrin (Josue, W. Erb) are 
not the result of the effect on the blood-pressure, but are due to a special toxic 
action such as is exerted by other substances of quite different nature (Heubner) . 

Seat of Action. — The question as to which elements of the vessel 
wall are affected by the vasoconstricting action of epinephrin may be 
discussed only in connection with the other actions of the drug. In 
this connection it was first shown by Wessely for the eye, and later 
by Langley and Elliot for all other vegetative organs, that in all of 
them epinephrin produced the same effects as are produced by stimu- 
lation of their sympathetic nerves, but never the same as those caused 
by stimulation of the other vegetative nerves. This striking paral- 
lelism renders it highly improbable that the action of this drug on 
the smooth muscles of the vessel walls and of the dilator pupilla?, etc., 
is a direct one on the muscles. It appears much simpler to attribute 
this action to the stimulation of the nerve-endings of the sympathetic 
system. A very important aid in the solution of this matter has been 
furnished by the above-mentioned experiments of Langendorff on the 
coronary vessels, which are not constricted by epinephrin but are 
dilated. According to the studies of Maass, moreover, vasodilators 
for the coronary vessels actually pass down in the accelerator nerve, 
while the vasoconstrictors lie in the vagus trunk. This anatomical 
fact, in conjunction with the action of epinephrin on the coronary ves- 



EPINEPHRIN 283 

sels, serves as another support of the hypothesis that epinephrin acts 
on the sympathetic nerve-endings and not on the muscles in the vessels, 
for we have no reason to believe that the muscles of the coronary 
vessels differ essentially from those of other vessels. 

The point at whicli epinephrin acts, however, cannot be those nervous struc- 
tures which degenerate after section of the nerve-trunks, for Langley found that 
epinephrin was still effective at a time when as a result of section of the nerve- 
trunk all the histologically differentiable nerve-endings had undergone degenera- 
tion. He, therefore, locates the action of epinephrin in a receptive intermediary 
substance lying between the nerve and the muscle. Inasmuch as we look upon the 
connection between the nerve and the muscle as an exceedingly intimate one, and 
we. possess no criterion for determining what belongs to the nerve and what does 
not, this hypothetical receptive intermediary substance must be considered as a 
part of the nerve-ending. 

Physiological Tests for Epinephrin. — The physiological importance 
of epinephrin has been established ever since it was proved that nor- 
mal blood-serum contained it. Although the exceedingly small amount 
of epinephrin normally present in the blood cannot be demonstrated by 
chemical methods, it is possible to show that serum exerts the charac- 
teristic physiological effects of epinephrin, and especially is this clear 
with the serum of blood obtained from the suprarenal veins. This 
was first incontestably demonstrated by Ehrmann, who found that 
serum obtained from the suprarenal veins exerted the same mydriatic 
action as epinephrin when it was applied to the enucleated frog's eye. 
0. B. Meyer and Schlayer found that blood-serum causes the same 
contraction of smooth muscles of the surviving artery as is caused by 
extremely dilute solutions of epinephrin. In the same fashion normal 
blood-serum causes an increase in the tone of a rabbit's uterus "sur- 
viving" in Ringer's solution, which is an extremely delicate object for 
testing epinephrin (Frdnkel), and Trendelenburg found that, when 
the blood-vessels of the frog were perfused with serum, the retardation 
of the flow was identical in every respect with that observed when 
very dilute solutions of epinephrin were perfused. 

While O'Connor has shown that other active substances contained 
in the serum are responsible for part of this effect, the greater activity 
of serum obtained from the suprarenal veins as compared with that 
obtained from other organs indicates that these physiological reactions 
of the normal serum are at least in part due to epinephrin. Thus, the 
Whrmann-Meltzer pupil reaction is strongly positive only when the 
serum from the suprarenal veins is used, and is not ordinarily pro- 
duced by the serum from the carotid or jugular. In this fashion it 
was demonstrated that the blood from the suprarenal veins actually 
contained more epinephrin than any other blood (Ehrmann) . Simi- 
larly such serum constricts the vessels of the frog much more strongly 
than doos serum from carotid (O'Connor) (see Fig. 31). Moreover, 
blood from the suprarenal vein when injected into a second animal 
produces ,i greater rise of blood -pressure than blood obtained from 
other vessels (Szymonovicz, Camus ct Langlois). The strongest evi- 



284 



PHARMACOLOGY OF CIRCULATION 



dence of a physiological secretion of epinephrin is the histological fact, 
observed by Arnold, that the granular chromaffin bodies, found in the 
medullary cells of the suprarenal gland, pass directly from these cells 
into the first beginnings of the suprarenal veins. 

Fig. 31 shows the course of the vasoconstriction produced in the 
surviving frog's vessels by serum from the carotid and by that from 
the suprarenal veins. That the stronger vasoconstricting effect of this 
last-mentioned serum is actually due to the presence of epinephrin, 
which has been secreted into these veins, is indicated by the destruction 
of the active substance if oxygen be passed through the serum for a 
number of hours, this ready oxidizability being characteristic of 
epinephrin. 

Physiological Significance for the Blood-pressure. — According to 
Tscheboksaroff, Asher, and Kahn, it would appear that the functional 
activity of the splanchnic nerve depends on the internal secretion of 
the suprarenal glands. Bilateral extirpation of these glands is fol- 




om adrenal veins 
it for G hours 



lowed by general prostration with a pronounced fall in the body tem- 
perature and progressive sinking of the blood-pressure, and is fol- 
lowed by death unless accessory suprarenals are present, or unless 
a sufficiently long period of time has elapsed between the extirpation of 
the first and second gland, to permit of a compensatory hypertrophy 
of the chromaffin tissue in other parts of the body (Brown-Sequard, 
Langlois, Szymonovicz, Hultgren u. Anderson, Strehl u. Weiss). 
However, it has been shown by Biedl that the importance of the 
suprarenals for the maintenance of life is not entirely dependent 
on the secretion of epinephrin, for the cortex of the gland also 
possesses vitally important functions, which perhaps consist in render- 
ing harmless the poisonous products of muscular activity {Langlois 
et Abelous). The great physiological importance of the suprarenals 
is also evidenced by the uncommonly rich blood supply of these tiny 
organs (Langlois, Flint) . 

From what has already been said, there can be no doubt that 
epinephrin aids in maintaining and regulating the normal peripheral 



EPINEPHRIN 285 

vascular tone. It would appear that a certain apparently constant 
amount of epinephrin is present in the Mood, and that, as there is a 
continuous inflow of this substance into the blood, a constant effect 
on the sympathetic nerve-endings is exerted, the epinephrin which 
has reached the cells being constantly destroyed, but that just entering 
them stimulating the nerve-endings (Straub u. Eretschmer). Inas- 
much as the histological studies of Wiesel have shown that the medulla 
of the suprarenal gland and the other chromaffin tissues stand in a 
close developmental relation to the sympathetic system, it would 
appear that this system provides for the maintenance of its own stimu- 
lation by itself producing the stimulating substance. 

Practical Applications. — The use of epinephrin to influence the 
cardiac action and the general distribution of the blood will be dis- 
cussed later. It is extensively employed as a local application to 
mucous membranes and bleeding wounds, especially in combination 
with cocaine, which also has, to a less degree, a vasoconstricting effect 
(seep. 124). 

BIBLIOGRAPHY 

Abderhalden u. Miiller : Ztschr. f . physiol. Chemie, 1908, vol. 58. 

Arnold: Virchow's Arch., 1866, vol. 35. 

Asher: Zentralbl. f. Physiol., 1910, vol. 24, No. 20. 

Bayliss: Journ. of Physiol., 1902, vol. 28. 

Biedl: Die irmere Sekretion, Wien, 1910. 

Blum: Pfluger's Arch., 1902, vol. 90, p. 617. 

Brown-Sequard : Compt. rend. Soc. de Biol., 1856, vol. 43. 

Camus et Langlois: Soc. de Biol., 1900. 

Cow: Journ. of Physiol., 1911, vol. 42, p. 125. 

Cushny: Journ. of Physiol., 1908, vol. 37, p. 130. 

Dakin: Journ. of Physiol., 1905, vol. 32, Proc. Physiol. Soc, p. 34. 

Ehrmann: Arch. f. exp. Path. u. Pharm., 1905, vol. 53, p. 97. 

Elliot: Journ. of Physiol., 1905, vol. 32, p. 401. 

Erb, W.: Arch. f. exp. Path. u. Pharm., 1905, vol. 53, p. 173. 

Exner, A.: Ztschr. f. Heilkunde, 1903, No. 12. 

Exner, A.: Arch. f. exp. Path. u. Pharm., 1903, vol. 50, p. 313. 

Falta u. Ivcovic: Wien. klin. Woch., 1909, No. 51. 

Flint: Hopkins Hospital Rep., vol. 9. 

Friinkel: Arch. f. exp. Path. u. Pharm., 1909, vol. 61. 

v. Frey, M. : Verhandl. d. Physik.-med. Ges. zu Wiirzburg, 1905. 

FrShlich, A.: Zentralblatt f. Physiol., 1909, No. 8. 

v. I -'firth: Ztschr. f. physiol. Chemie, 1898. vol. 26, p. 15. 

Gerhardt: Arch. f. exp. Path. u. Pharm., 1900, vol. 44, p. 161. 

'Gottlieb: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 99. 

2 Gottlieb: Arch. f. exp. Path. u. Pharm., 1900, vol. 43, p. 286. 

Halsey: Trans, of Amer. Phys., 1905. 

Herter u. Wakeman: Virchow's Arch., 1902, vol. 169, p. 479. 

Hi ul. iK r: Ergebnisse der inneren Medizin, 1908, vol. 1. 

Hult^ren u. Anderson: Skand. f. Physiol., 1899, vol. 9. 

Jobu6: La Presse mfidicale, Nov. IS, L903. 

Kulm, P. II.: I'llfi-'r's Arch., 1911. vol. 140, p. 299. 

Langendorff: Zentralbl. f. Physiol., 1908, vol. 21, No. 17. 

Langley: Journ. of Physiol., 190], vol. 27, p. 237. 

Lengley: Journ. of Physiol., 1905, vol. 33, p. 374. 

Langlois: Les Capsules Burrenales, 1'aris, 1897. 

Langlois: Arch, de Physiol., 1894. 

Langley et Abelous: Arch.de Physiol.. 1892^-93. 

Loewi u. Meyer: Arch. f. exp. Path. u. Pharm., 1905, vol. 53, p. 213. 



286 PHARMACOLOGY OF CIRCULATION 

Maase: Pfliiger's Arch., 1889, vol. 74, p. 2S1. 

Meyer, O. B.: Ztschr. f. Biol., 1907, vol. 30. 

Miller: Jour, of A.M.A., 1909. 

O'Connor: Heidelberg, unpublished experiments. 

Oliver and Schaefer: Journ. of Physiol., 1895, vol. 18, p. 230. 

Pick, Fr.: Arch. f. exp. Path. u. Pharm., 1899, vol. 42. p. 399. 

Sehlayer: Deut. med. Woch., 1907, No. 4G, p. 1897. 

Stoltz: Ber. d. Chem. Ges., 1904, vol. 37, p. 4149. 

Straub: Verh. d. Physik.-med. Ges. in Wiirzburg, 1907. 

Straub u. Kretschmer: Arch. f. exp. Path. u. Pharm., 1907, vol. 57, p. 423. 

Strehl u. Weiss: Pfliiger's Arch., 1901, vol. 86, p. 107. 

Szymonoviez: Pfliiger's Arch., 189G, vol. G4, p. 97. 

Trendelenburg: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 161. 

Tscheboksaroff: Pfliiger's Arch., 1910, vol. 137, p. 59. 

Velich: Wien. med. Blatter, 1896. 

Wesselv: Ber. ophth. Ges., Heidelberg, 1900. 

Wiesel': Anat. Hefte, 1902, vol. 19. 

The digitalis bodies are also to be numbered among the substances 
which, cause constriction in important vascular systems by a local 
action. "With them, too, this action is a local one in the vessel wall, 
for the vasoconstriction produced by them occurs after section of the 
cervical cord and pithing of its lower portions. Here, too, it is not 
possible to determine definitely which elements in the vessel wall are 
acted upon, but it appears justifiable to consider the action on the 
vessels as analogous to that on the heart, which, in point of fact, is 
only a more highly specialized artery. That the action of digitalis 
on the vessel walls is a local one, taking place in the vessel walls 
themselves, was indicated by the first observations made by perfusing 
cold- and warm-blooded organs {Donaldson and Stevens, Robert) with 
digitalis substances, for in these experiments the blood stream was 
retarded after addition of such drugs to the perfusion fluid. As 
long as such evidence depended only on experiments on surviving 
organs, it remained cptestionable whether the same held good for living 
animals. Since that time the vasoconstricting action in the intact 
mammal has been definitely proved by the use of various experimental 
methods. 

In an indirect fashion Lander-Brunt on and Tunniclijfe reached the conclusion 
tliat the vessels were constricted by observing the retarded flow of blood through 
the narrowed arterioles into the veins. If the heart in the intact circulation 
be stopped by stimulation of the vagus, the rapidity and the extent of the 
fall in pressure in the aorta depend on the resistance in the vessels against which 
the large arteries empty themselves during the persistent diastole of the heart, 
and if the blood path is widely opened the outflow is rapid and the blood-pressure 
sinks rapidly. With contracted vessels, on the contrary, this must take place 
more. slowly. In the experiments of these authors comparison of the behavior 
of the blood-pressure during the stoppage of the heart induced by vagus stimu- 
lation showed an appreciably slower fall after injection of digitalis than occurred 
before. 

Differences in the Degree of Vasoconstriction Induced in Different 
Organs. — A knowledge of the behavior of the different vascular sys- 
tems under the influence of digitalis has been obtained by means of the 



DIGITALIS AND THE VESSELS 



287 



plethysmography as well as by the method of measuring the amount 
of blood passing through the separate vascular systems as described 
on page 242 {Bradford and Phillips, F. Pick). In these experiments 
it was demonstrated that after very small doses the vasoconstriction 
affects chiefly the visceral vessels (Gottlieb u. Magnus), while other 
vascular systems — for example, the vessels of the skin and muscles, 
as also the renal vessels — dilate (Loewi u. Jonescu) . This difference 
in behavior is due to a quantitatively different susceptibility of the 
different vascular systems, which may best be demonstrated in per- 
fusion experiments on surviving organs. Those concentrations of 
digitoxin and strophanthin, which when perfused dilate the renal 
vessels, cause a constriction of the intestinal vessels, while the vessels 
of the skin and muscles are entirely uninfluenced and are constricted 




(iinniinnjinnnniin^ 

Flo. 32. — Effects of strophanthin on blood-pressure and on volume of spleen and leg. 

only by much higher concentrations (Kusztau, Fahrenkamp) . It may 
be concluded that in the living animal the vessels of the extremities 
will be dilated during the early stages of digitalis action, because 
the blood will be mechanically driven out of the visceral vessels when 
these are constricted while the vessels in the extremities are as yet 
uninfluenced by the drug. All these vasomotor reactions are in part 
caused by depressor reflexes, which cause a distinct dilatation of the 
vessels in the extremities in order that in them a place may be found 
for the blood forced out from the visceral vessels (see Fig. 32) . 

The behavior of the kidney vessels previously mentioned demon- 
strates that digitalis bodies may exert a vasodilating action which, 
as shown by Locwi and Join sen's experiments on the kidney isolated 
from its nerves and by Kasztan's and Fahrenkamp's on surviving 
organs, is a direct one on the vessel walls. In the vessels of the intes- 



288 PHARMACOLOGY OF CIRCULATION 

tine almost the only action of the digitalis bodies is that of vasocon- 
striction. 

Quantitative Differences between the Different Digitalis Bodies. — 
All the members of the digitalis group have a vasoconstricting action, 
which, however, is developed to a different degree in different members 
of the group, being developed in the case of digitoxin and much 
less so in digitalin, strophanthin, and others. 

After toxic doses of these substances, but especially of digitoxin, 
all parts of the systemic circulation take place in the vasoconstriction, 
and the dilatation of the peripheral systems does not occur — or is 
developed only as the action passes off and the blood-pressure rises 
markedly. With doses causing a somewhat less intense effect, the 
intestinal and hepatic vessels and usually also the renal vessels are 
constricted, while in the periphery of the body, as well as in the 
brain, the blood flow is improved. 

Finally, very small doses produce only a change in the distribution 
of the blood "without rise in the general pressure, the intestinal vessels 
being constricted and the renal vessels being dilated {Loewi and 
Jonescu). 

BIBLIOGRAPHY 

Bradford and Phillips: Journ. of Physiol., 1887, vol. 8, p. 117. 

Donaldson and Stevens: Journ. of Physiol., 1883, vol. 4, p. 165. 

Fahrenkamp: Arch. f. exp. Path. u. Pharm., 1911. 

Gottlieb u. Magnus: Arch. f. exp. Path. u. Pharm., 1901, vol. 47. 

Kasztan: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 406. 

Kobert: Arch. f. exp. Path. u. Pharm., 1886, vol. 22. 

Lauder-Brunton and Tunnicliffe: Jour, of Physiol., 1896, vol. 20, p. 354. 

Loewi u. Jonescu: Arch. f. exp. Path. u. Pharm., 1908, vol. 59. 

Pick, P. : Arch, f . exp. Path. u. Pharm., 1899, vol. 42. 

PERIPHERALLY ACTING VASCULAR DEPRESSANTS 

Amyl Nitrite. — Numerous drugs and poisons possess a depressing 
action on the vessel walls. In particular, amyl nitrite and other 
nitrites, in addition to acting on the vasomotor centres, cause, even in 
non-poisonous dosage, a demonstrable peripheral vascular paralysis. 

The narcotics of the alcohol group, especially chloroform and 
chloral hydrate, show a similar peripheral action only in such high 
concentration that it is of significance only in most severe poisoning. 
This effect is shown in surviving organs by the great increase in the 
blood flow when these drugs are perfused. In perfusion experiments 
an effect on the vessels occurs only with a chloroform content of 0.1 
per cent. {Sherrington and Sowton), and, as a concentration of from 
0.06-0.07 per cent, of chloroform quickly kills by paralysis of the 
respiration, this peripherally induced dilatation in contradistinction 
to the central vasomotor paralysis is of no practical significance for 
the action of chloroform. 

Capillary Dilators. — It is probable that toxic actions on the 
vessel walls are often not limited to the arterioles, but that the calibre 



PERIPHERAL VASODILATORS 289 

of the capillaries may also be affected. This has been demonstrated 
for the vasodilating action of arsenic and antimony, as well as for 
other metal salts and other substances, among -which is sepsin, a very 
poisonous base produced by certain bacteria. The point of predilective 
action of these capillary poisons lies in the walls of the intestinal 
vessels. That this vasodilatation is of peripheral origin is demon- 
strated by the fact that the excitability of the splanchnic nerve for 
electric stimuli constantly diminishes as the fall in blood-pressure 
progresses (Bohm u. TJnterb ringer, Pistorius). The extreme 
hyperemia of the intestines resulting from these toxic actions, the 
extravasations of blood, and the alterations in the capillary walls 
make it clear that these poisons exert an elective action on the capil- 
laries. 

The elective action which some drugs exert on special vascular sys- 
tems is the basis of their therapeutic application. 

Yohimbin is a good example of a drug exerting such a peripheral 
elective action on vessels, which occurs even after previous section 
of the nerves, but affects only certain vascular systems, or at least 
is especially pronounced in them. It causes a dilatation of the vessels 
in the genital organs, which may be demonstrated by the increased 
flow of blood through the dorsal vein of the penis. Simultaneously 
the vascular systems of the skin and kidney dilate, while other vessels 
— for example, those of the spleen — contract. The aphrodisiac action 
of yohimbin (p. 219) is due partly to this increased blood flow to the 
genital organs, and partly to an augmentation of the reflex excitability 
of the centres of erection (Franz Mutter). 

Caffeine also exerts a local elective action on the renal and the 
cerebral vessels, while the dimethylxanthines (theobromine, theocin, 
etc.), as well as digitalis, act in a like manner on the renal vessels. 
Caffeine and theobromine, and perhaps also amyl nitrite, have a 
specific power of dilating the coronary vessels, an action of great sig- 
nificance for the flow of blood through the tissues of the heart. 

Avascular Alterations from Local Applications. — Aside from 
such elective pharmacological actions in the different vascular systems, 
local vasodilatations and vasoconstrictions, resulting from a direct 
contact of chemical substances with the vessel walls, are of considerable 
importance. Thus, the astringents (see p. 213), when not too highly 
concentrated, produce a constricting effect on the vessels at the place 
of application. The same substances in higher concentrations, as well 
as all i nil ants, dilate the blood-vessels locally. Further, in inflam- 
mation, local vasodilatation may be caused either by irritating sub- 
stancea penetrating from the exterior or by products of the pathologi- 
cal tissue changes. The influence of increased function is of a similar 
nature, for there is certainly a local cause for the increased inflow 
<>f blood which occurs during activity of an organ, caused probably 
by some of the products of the metabolism of the organ exerting a 
19 



290 PHARMACOLOGY OF CIRCULATION 

vasodilating action. It may be that the vasodilatation, which Bier 
has shown to result from temporarily cutting off the blood supply, 
is brought about in an analogous fashion. Finally, in this connection, 
it is proper to state that cold constricts while heat dilates the vessels. 

BIBLIOGRAPHY 

Bohm u. Unterberger : Arch. f. exp. Path. u. Pharm., 1874, vol. 2, p. S9. 
Heubner: Arch. f. exp. Path. u. Pharm.. 1907, vol. 56, p. 370. 
Miiller, Franz: Arch. int. de Pharmaeodyn. et de Ther., 1907, vol. 17, p. 81. 
Pistorius: Arch. f. exp. Path. u. Pharm'., 1883, vol. 16, p. 188. 
Sherrington and Sowton: Labor. Report., 1903, vol. 5, Univ. Liverpool. 
Sherrington and Sowton: Brit. Medic. Journ., 1904, vol. 2, p. 102. 

THE EFFECTS ON THE CIRCULATION AS A WHOLE PRODUCED 
BY DRUGS ACTING ON THE HEART AND ON THE VESSELS 

The indications for the administration of drugs acting on the 
circulation are found in the presence of disturbances of the heart 
function or of alterations in the distribution of the blood, resulting 
from vascular paresis or vascular cramp. 

Disturbances of the Cardiac Function. — The heart, as the motor 
organ of the circulation, has the task of driving the blood through 
the arterial and venous portions of the systemic and pulmonary circu- 
lations in quantities sufficient to supply the needs of all the organs. 
It is not able to do this — 1st, if it is beating too slowly; 2d, if both 
ventricles empty themselves too incompletely; or, 3d, if either of the 
two ventricles is no longer contracting forcibly enough to expel its 
contents in a normal fashion. These different types of insufficient 
heart function lead necessarily to somewhat different results, for in 
case of too slow action of both halves of the heart, or in case of an 
equally incomplete emptying of both ventricles, there will result only 
a dangerous retardation of the blood flow in both circulations. On 
the other hand, in case one ventricle is unable to empty itself com- 
pletely, the distribution of the blood throughout the body will become 
abnormal and stasis will result. 

In an acute anamia from hemorrhage both sides of the heart re- 
ceive and pump out too small a quantity of blood. Also in enfeebled 
conditions of the heart, such as may be caused by numerous exogenous 
poisous, as well as by the toxins of infection, the contractions of both 
ventricles become equally incomplete and feeble. In both cases the 
skin becomes pale and the extremities cold and the brain is poorly 
supplied with blood. As this organ is extremely sensitive to dis- 
turbances of its circulation, interference with its blood supply quickly 
results in a feeling of faintness. "While the other organs also suffer 
more or less as a result of the retardation of the blood flow, the heart 
especially suffers on account of the insufficient circulation in the 
coronary vessels. 

Stasis. — When one ventricle is beating feebly while the other 
continues to function normally, or when the efficiency of one is im- 



THEORY OF DIGITALIS ACTION 291 

paired to a greater degree than that of the other, quite different con- 
ditions arise. If, for example, the left ventricle contracts incompletely, 
on the one side, too little blood flows iuto the aorta and, on the other, 
the auricle is unable to empty itself completely into the ventricle on 
account of the residual blood left there at the end of the incomplete 
systole. The blood, therefore, accumulates first in the left auricle 
and then in the pulmonary vessels. If, now, the right heart continues 
to pump out blood in the same amounts as before, the left heart must 
soon become dilated and the stasis in the pulmonary vessels will in- 
crease, dyspnoea and, with marked stasis, oedema of the lungs resulting. 

If it be the right ventricle which is affected, the blood accumulates 
in the right auricle and the great veins, and especially in the capil- 
laries of the whole portal system, which is immediately affected by 
every rise in pressure in the vena cava. Congestion of the liver, 
impaired renal circulation with its resulting oliguria, and stasis in the 
vessels of the intestines result, and ascites may develop. 

Effects on the General Blood Flow. — With one of the ventricles 
contracting inefficiently, the arterial portion of its vascular system is 
inefficiently filled, and the blood accumulates and remains in the 
veins from which it receives its supply. This blood is, as it were, 
removed from the circulation, so that the blood flow in all the tissues 
is diminished. "With marked venous stasis the capillaries are also 
overfilled. Cyanosis results when too little blood flows through the 
lungs. 

Circulatory Insufficiency Due to Cardiac Disease. — Such conditions 
arise both in disease of the myocardium and of the valves, unless the 
resulting interference with the circulation of the blood is more or 
less completely compensated. The first compensatory change, is 
brought about by hypertrophy of the muscles of the overfilled and 
weakly contracting part of the heart or of the heart chamber next 
involved, which is thus enabled to pump out the blood in sufficient 
amounts and with sufficient force to overcome any unfavorable con- 
ditions in the circulation. When, as a result of progressive valvular 
or myocardial disease or of impaired nutrition of an overtaxed heart, 
compensation is finally broken down, stasis develops in the pulmonary 
or systemic systems or in both, and its symptoms — dyspnoea, cyanosis, 
congestion of the liver, oliguria, ascites, oedema, etc. — result. Under 
these conditions, digitalis is the« sovereign remedy. 

THEORY OF THE ACTION OF DIGITALIS 
The separate pharmacological actions of digitalis having been 
discussed, it, is now in order to consider the general effects produced by 
these separate actions. As stated in previous sections (see pp. 264-5), 
the drugs of tliis group enable the heart to accomplish more work 
with each contraction, and proofs have been presented (see p. 286) 
that thus the minute volume of blood pumped is, under certain condi- 



292 PHARMACOLOGY OF CIRCULATION 

tions, increased. It has also been demonstrated that, simultaneously 
with such alterations of the heart function, vasoconstriction occurs 
in various vascular systems, and that these primary and direct digi- 
talis actions tend to bring about a rise of blood-pressure. A third 
digitalis action — that is, a retarding of the cardiac action, which 
appears in the early stages — works in opposition to these two blood- 
pressure raising actions (see p. 215). 

The retardation of the pulse is one of the first of the digitalis 
effects to appear, and it is so well developed after therapeutic doses 
of the drug that Traube originally considered this the most important 
result produced by therapeutic doses. He also recognized it as due 
chiefly to a central stimulation of the vagus, which view is held by 
many at the present day. Lenz's and Traiibe's own later recognition, 
as a result of experiments on animals, of the great rise in blood- 
pivssure caused by effective doses led to his abandonment of this view, 
and he concluded that the slowing of the heart action was simply 
one of the symptoms resulting from the general action on the circu- 
lation, a symptom, moreover, of considerable importance, for it sup- 
plies a convenient means for determining the degree of digitalis action 
which has been produced. 

Rise op Blood-pressure. — "With the discovery of the rise in blood- 
pressure which in normal animals is caused by digitalis, the doctrine 
of digitalis actions entered on a new phase, and this action has since 
then exerted a preponderating influence on the views of its pharmaco- 
logical action. The therapeutic effects of the drug have been attributed 
to the improvement of the blood-pressure and the better filling of 
the arteries resulting from its use, and indications for its employment 
have been sought in conditions of low blood-pressure. However, as 
will soon be seen, modern clinical observations force an abandonment 
of this view, so that the explanation of its curative action is to be 
found not so much in a raising of the blood-pressure as in an alteration 
of the distribution of the blood. 

However, in order properly to understand the complex actions of 
digitalis and their influence on the blood-pressure and the distribution 
of the blood throughout the body, it is best to start with a considera- 
tion of the augmentation of blood-pressure which in animals regularly 
results from administration of toxic doses. 

The increased "pulse volume" of the heart will of itself tend to 
raise the aortic blood-pressure. This has been demonstrated in the 
most indisputable fashion by Bock, who, making use of his "heart- 
lung" circulation, found that after injections of digitalis bodies the 
blood-pressure quickly rose, although at first the heart-rate was un- 
changed (see Fig. 33 and p. 240). Such results prove that increase of 
the pulse volume of the heart is, at any rate, one of the causes of 
the increased blood-pressure. 

The augmentation of the pulse volume caused by digitalis may be 



THEORY OF DIGITALIS ACTION 



293 



due to a more extreme relaxation of the heart without any increase 
of the contractions, or it may be that the ventricle, which was not 
contracting maximally, under the influence of the drug is enabled to 
contract more completely than before. Both factors may work to- 
gether, but much speaks for the view that a more complete contrac- 
tion is the chief factor in increasing the pulse volume of the heart. 
For example, in Bock's experiment "the rise in blood-pressure was less 
strongly pronounced in strongly beating hearts and more pronounced 
in feebly contracting ones." Under normal conditions, the contrac- 
tions of the mammalian heart are not complete, — that is, it does not 
contract to such a degree as completely to obliterate the ventricular 
lumen. Moreover, as a result of any damage done to it by such 
manipulations as are involved in exposing the heart or in the prepara- 
tion of the great vessels or in similar procedures, its contracting 
powers are further impaired. Therefore, at the end of each systole 
the ventricle retains a certain amount of blood. In Bock's experi- 
ments, when the contractions were relatively complete, approximating 



5 mins. 
before 


1 min. 
before 


1%/ 

1 min. after 


mm. 

4 rnins. after 



Fio. 33. — Blood-pressure in "heart-lung" circulation before and after digitalis body. 

the normal, the digitalis could improve the contractions to a slight 
degree only. If, however, the heart were beating poorly and the 
contractions were abnormally incomplete, the favorable influence 
exerted on the contractions was more pronounced and the blood- 
pressure rose markedly. 

The " Langendorff " isolated heart always contracts less completely than a 
heart in situ, for the amount of blood flowing through its vessels is always far 
smaller than that circulating through the vessels of the heart in the intact 
circulation. It is probably for this reason that digitalis exerts such a favorable 
influence on its contractions (Magnus u. Howton) . 



Cushny's observations on the intact circulation of dogs and cats 
agree with this conception. Using a cardiometer (a plethysmography 
mstrument), he estimated the amount of blood forced out during 
each systole, and found that digitalis caused a distinct increase of 
tin' pulse volume of the heart, which, in his experiments, was undoubt- 
edly somewhat weakened. This was graphically recorded, and must 
be attributed chiefly to an influence on the extent of the contractions, 
for the curve showed Hi is to be distinctly increased while the relaxa- 
tion during diastole, waa but slightly influenced. 



294 PHARMACOLOGY OF CIRCULATION 

The rise in blood-pressure is, however, not only the result of aug- 
mentation of pulse volume of the heart, but is also in part the result 
of vasoconstriction. 

Tigerstedt, by the use of his Stromuhr (current clock), determined 
the amounts of blood pumped into the aorta during the unit of time, 
before and after the administration of digitalis, recording the carotid 
pressure at the same time, and found that, as a rule, the "second 
volume" of blood expelled by the heart increased simultaneously with 
the rise in blood-pressure which followed the injection of digitalis. 
However, in some cases where the pressure rose markedly, the ' ' second 
volume" of the blood expelled was not increased, and in all cases it 
was diminished again at a period when the blood-pressure was still 
rising. 

The analysis of the "pressor" effect thus shows that the influence 
of "heart work," or "heart performance," and the constriction of 
the more important vascular systems go hand in hand. As a result of 
the joint effect of these two factors, the blood-pressure would neces- 
sarily be raised under all conditions, were it not for the fact that 
digitalis and its congeners exert a third fundamental action on the 
circulation, that of pulse retardation, which, in the first stages of 
the digitalis action, acts in opposition to the two other actions of the 
drug. In experiments on animals, the slowing of the heart thus caused 
may be so pronounced as to result in a diminution in the volume of 
blood pumped out per minute, in spite of the increase in the amount 
pumped by each contraction. It may thus happen that at first the 
blood-pressure does not rise (after injection of digitalis) so long as 
the heart rate is slowed, but it always rises if the vagi be cut or when 
at a later period the heart becomes insusceptible to the inhibitory 
influence of the vagus. 

Regulatory Action. — Still a fourth fundamental action of digi- 
talis, the regulation of arrhythmic cardiac action, may be demonstrated 
in both the intact circulation and the artificially perfused mammalian 
heart as well as in the "heart-lung" circulation. This action is 
present, however, only in the early stages,* and, as a matter of fact, 
in the later stages irregularity of the pulse occurs and is a typical 
symptom of the 

Toxic action of digitalis, developing some time before the blood- 
pressure, usually quite suddenly, dropping to zero as the heart dies. 
If the complex fashion in which these different pharmacological actions 
of digitalis mutually affect each other be considered, the course of the 

* [This sweeping statement is correct only in so far as it refers to experiments 
in animals or in certain clinical conditions. As a matter of fact, in various 
clinical conditions, such as auricular fibrillation very often and premature 
systolic arrhythmias occasionally, a decided improvement of the regularity of 
the heart action is an expression of the full and desired therapeutic action of 
digitalis and its congeners (see translator's notes, pp. 2(>6, 300). — Tr.] 



THEORY OF DIGITALIS ACTION 



295 



blood-pressure curve (Fig. 34) may be understood. Two stages may 
be differentiated: 

1. A stage during which the heart action is strengthened and 
slowed, which may be called the therapeutic stage, for these early 
actions are alone of therapeutic value. Regulation of the heart action, 
augmentation of the pulse volume of the heart, constriction of im- 
portant vascular systems with simultaneous compensating dilatations 
in others, and slowing of the pulse, characterize this stage. The blood- 
pressure, depending on the extent to which the pulse is retarded, may 
rise slightly or remain constant [or may fall somewhat. — Tr.]. 

2. A toxic stage in which the blood-pressure, in spite of persisting 
pulse retardation, and later during a sudden acceleration, continues 
to rise. In this stage the vasoconstriction is chiefly responsible for the 
rise in pressure, for the work performed by the heart is at this time 
lessened. Finally the heart action becomes irregular and the blood- 
pressure falls.* 



a 

Normal 
blood- pressure 


Digitalis 
action com- 
mencing 

,/\AA/W^ 


o 


d 


e 

vvv 



Fio. 34. — Blood-pressure curves showing the effects of digitalis in a dog (Williams). 



It is thus seen that in the first stage of digitalis action, the only 
one having a bearing on its therapeutic usage, the blood-pressure is 
not necessarily raised. Obviously the conditions in the healthy man 
are similar. Frankel observed in healthy persons, used as test objects, 
a rise in blood-pressure only after the compensating pulse slowing had 
been prevented by administration of atropine. Moreover, in patients 
in whom stasis is present the curative action of digitalis usually mani- 
fests itself without causing any augmentation of blood-pressure. We 
owe the establishment of this important fact to the development of 
methods for the bloodless determination of blood-pressure (see p. 236), 

* [The irregularity in the heart's action at tliis stage may be the result either 
of more or less complete heart-block, or of premature systoles (due to increased 
irritability of the ventricle), or to auricular fibrillation (due to the digitalis), 

or to combinations of two or all of these factor*. — Tb.1 



296 PHARMACOLOGY OF CIRCULATION 

for by their employment it has been shown that digitalis may remove 
conditions of stasis without causing a rise in pressure (Sahli, Lang). 
This is also the ease after intravenous injection of digitalis or similar 
drugs (Frankel u. Schwartz), the observations made when the drug is 
thus administered being especially valuable because the effects on the 
circulation ensue with the same rapidity as in experiments on animals 
and consequently may be exactly determined. 

Altered Distribution of the Blood. — Inasmuch as digitalis is 
able to remove conditions of stasis without necessarily markedly in- 
fluencing the blood-pressure, the improvement of the circulatory 
function cannot be attributed to an augmentation of the arterial 
pressure. The curative action of these drugs under such conditions 
should rather be attributed to the fact that the abnormal distribution 
of the blood and the stasis are replaced by normal conditions. In 
order to understand this more completely it is necessary to observe 

THE ACTION OF DIGITALIS IN PATIENTS SUFFERING FROM HEART 
DISEASE. 

While it is true that the pharmacological actions of these drugs 
are fundamentally the same in the normal and pathological circula- 
tions,* in the presence of pathologically altered function the results 
produced by these actions present themselves quite differently. It 
must be quite clear that the conditions obtaining in cases of cardiac 
s insufficiency are especially calculated to render the very first stages 
of digitalis cardiac action beneficial, for here the drug is acting not 
on a ventricle beating with the normal optimal efficiency but on one 
contracting inefficiently. Any disparity in the performance of the 
two ventricles will be removed by improvement of the function of that 
portion of the heart which is not working well. As a result the 
venous stasis will be relieved by a shifting of the blood from the venous 
side of the circulation over to the arterial portion. 

Under pathological conditions the slowing of the pulse produces a 
distinctly more beneficial result on the total performance of work by 
the heart than is the case under conditions of health. While in the 
healthy heart digitalis reduces the pulse below the normal, in cardiac 
disease, whenever it produces its desired effect, it usually brings it 
back to the normal. The effect of such action on the circulation is 
entirely different in the two conditions, for, as shown by the investi- 
gations of Frank and von Hofmann, the heart beats with maximum 
efficiency when beating at its normal rate. The simple inspection of 
the accompanying diagrammatic curves, representing the changes in 
the ventricular volume during a cardiac cycle (Fig. 35), demonstrates 
that much less blood is expelled by heart-beats following each other 
with abnormal rapidity than is the case when the rate of the heart 
action is about normal. _____^ 

* See translator's note, pp. 2CG, 300. 



THEORY OF DIGITALIS ACTION 



297 



The ordinates in the figure represent volumes, the abscissa, time, and the 
highest point of the curve corresponds to the most complete contraction. The 
amount of blood expelled at each period of the systole, or the amount received 
during the diastole, is represented by the difference in height of the ordinates. 
With a normal frequency of the heart action, the new contraction of the heart 
starts at that point of the volume curve A-B which corresponds to the maximum 
amount of blood which may be expelled by the ventricle. During pathologically 
rapid heart action, on the other hand, the diastolic relaxations become incomplete, 
because at the moment of the recurrence of a new contraction — for example, at 
the height of lines b and c — the heart has had time for only incomplete relaxation 
when the next contraction begins. 

A lessened frequency of the pulse, therefore, permits of better 
contraction of the whole cardiac cycle and of better refilling of the 
ventricles. "When beating at a moderate rate, the heart not only per- 
forms more work in the unit of time than it does when beating rapidly, 
but it performs this work more economically, as it can utilize its 
energy more completely. 




The lessening of the pulse frequency acts, therefore, in the same 
sense as the more powerful contraction of the heart. For this reason 
it would appear that digitalis should bring about a rise in blood- 
pressure, especially in conditions of stasis. Actually, however, in 
cardiac disease, blood-pressure in the aorta is not materially increased 
by digitalis, in spite of the important increase of the volume per 
second which is expelled by the heart. This must be due to the 
peculiar conditions obtaining in the pathological circulation. In all 
probability important vascular systems become more dilated than they 
were before the stasis was relieved. 

This view agrees with all that has been ascertained about the 
behavior of the vessels in conditions of stasis. In conditions of cardiac 
insufficiency, as a rule, the arteries exhibit a tendency to become con- 
stricted, their stronger tonus keeping the blood-pressure high. The 
cause of this vasoconstriction has not yet been fully cleared up, but 
certainly a role is played here by the carbonic acid which is present 
in abnormal amounts in the blood. Moreover, the absence of the re- 
flexes which ordinarily keep the peripheral resistance low when the 
vascular system is well filled must be of importance. However that 



298 PHARMACOLOGY OF CIRCULATION 

may be, in cardiac insufficiency a sort of vascular cramp must be 
assumed to be present before the action of digitalis develops. As the 
circulation in the lungs improves under the influence of digitalis, the 
asphyxia, and with it the abnormal contraction of the vessels, passes 
off, and, as the heart is now once more filling the systemic arteries 
more completely, the depressor nerve again exerts its function as a 
safety-valve and dilates the previously constricted vessels. It is thus 
evident that under such pathological conditions digitalis acts indirectly 
as a vasodilator. 

Does Digitalis Under Clinical Conditions Cause Vasoconstric- 
tion? — As, on the other hand, experiments on the normal animal 
have shown that digitalis exerts a direct constricting action on the 
vessels, the question arises : Does this occur after therapeutic doses or 
only after the administration of those larger toxic doses which produce 
augmentation of the blood-pressure? 

In animal experiments, at least, the vasoconstriction in the portal 
systems and the dilatation of the renal vessels do not occur later than 
those on the heart, but at the same time, and are observed after doses 
producing hardly any effect on the blood-pressure. As perfusion 
of surviving organs permits of comparing the relative susceptibility 
of the vessels and the heart, it has. been shown by this method that 
solutions of digitalis and of strophanthin, which may be perfused for 
a long time through the heart without harming it, promptly constrict 
the intestinal vessels and at the same time dilate the renal arteries 
(Fahrcnkamp). In these experiments the effects on the vessels and 
the improvement of the contraction of the heart, with an increase 
of its "minute volume," occur at the same time. From such experi- 
ments, it seems probable that in the living body also the dilatation of 
the renal vessels and the contraction of the intestinal vessels occur 
during the same stage of the pharmacological action as do the favor- 
able effects, on the cardiac function. 

Recent observations made on normal men by 0. Midler, Yagt, and 
Eychmiiller do not agree with this view. These authors were not able 
to demonstrate a constriction of the intestinal vessels after intra- 
venous injection of digitalis bodies, although a distinct but slight 
effect on the heart was produced. As these doses also produced no 
diuretic effect, they therefore were not large enough to cause dilatation 
of the renal vessels in healthy subjects. It was not possible to observe 
the behavior of the intestinal vessels in patients with cardiac disease, 
in whom the same doses produced pronounced effects on the heart and 
increased diuresis. It appears to the authors (G. and M.), however, 
that the conditions obtaining in a pathologically disordered circu- 
lation are too complicated to justify a conclusion that vasomotor 
changes do not occur in internal organs simply because the plethysmo- 
graphy curves obtained from the arm fail to indicate their occurrence. 

Tn cardiac disease the effects produced on the heart function appear 



THEORY OF DIGITALIS ACTION 299 



the vasoconstricting action on the vessels of the intestines and liver 
also appears to be beneficial. The clinical picture observed in patients, 
in "whom stasis due to cardiac disease is present, indicates, as empha- 
sized by Sahli, that not only the great vessels but also the whole 
portal system is over-distended with blood. Vasoconstriction in this 
system — which, as is well known, may contain extremely large amounts 
of blood — can be of great assistance to the heart by starting this 
stagnating blood to flowing again so that it may aid in filling other 
vascular systems. 

Against the view that the vascular actions of digitalis play any 
part in causing the benefits obtained from its therapeutic employment, 
objection has been raised, on the assumption that a vasoconstriction 
entails the burdening of the heart with a great task, and that therefore 
drugs of the digitalis group would be poor agents to use to aid a strug- 
gling heart if they increase the resistance against which the heart must 
expel its contents. This objection would be justified if these drugs, 
in therapeutic dosage, caused a general vasoconstriction. However, 
small therapeutic doses affect practically only the vessels most sus- 
ceptible to their influence, namely, those of the portal system. As the 
blood is thus forced from the vessels of the intestines and liver into 
other vascular systems, which are not constricted by these doses, — 
for example, into the renal vessels, which are in fact dilated under the 
influence of digitalis, — the resistance of the total cross-section of the 
vascular tree need not be increased to an extent greater than is com- 
pensated for by the increased efficiency of the heart action. 

Behavior of the Renal Vessels. — A second weighty objection rests 
on the behavior of the urinary secretion, for the increased diuresis 
speaks against any vasoconstricting action in the kidney, for any 
diminution of the blood flow through the kidney ordinarily causes 
diminished secretion. However, Loeivi and Jonescu have shown that 
the renal vessels, in contradistinction to the vessels of the intestines, 
are not contracted but are dilated by the small doses of digitalis, or 
other members of this group, which correspond to those used in thera- 
peuties. Very small doses of strophanthin, while causing a constric- 
tion of the intestinal vessels, produce little or no change in the blood- 
pressure, but still they stimulate diuresis. Moreover, the surviving 
renal vessels are dilated by the digitalis bodies in concentrations which 
constrict the intestinal vessels, and are constricted only by much 
stronger solutions I p. 287). The renal vessels are, therefore, one of 
the vascular systems which profit by the forcing out of the blood 
from the primarily constricted portal system. 

From the above it would appear that vasomotor effects way well 
piny a role in the therapeutic use of digitalis. As a result of the fact 
that, if stasis be present, the vasoconstricting action is more pro- 
nounced in the vessels of the portal system, a new redistribution of 



300 PHARMACOLOGY OF CIRCULATION 

the blood occurs, the blood being forced along not only from the 
veins into the arteries of the general circulation but also from the 
passively congested liver and intestines into other parts of the body. 

In still another way the actions on the vessels may be of moment. Recent- 
investigations (Hasebroek, Griitzner) make it probable that the active rhythmic 
contraction of the smallest vessels contributes to the maintenance of the circu- 
lation. If this be true, the action of digitalis on the vessels may be of value as 
aiding in forcing the blood along in the capillaries, and the absorption of oedema 
may thus be facilitated. 

A consideration of the conditions obtaining in pathological dis- 
turbances of the circulation thus leads to the following conception 
of its beneficial therapeutic action : Digitalis enables a ventricle, which 
has become insufficient, again to contract more completely, and brings 
about a better flow of blood through the organ. This results in the- 
disappearanee of the vasoconstriction in the large vascular systems 
which, in spite of existing stasis, has maintained the blood-pressure. 
^Yit]^ the restoration of an efficient functional activity of the heart, the 
conditions of blood-pressure and blood flow return to the normal^ 
and the blood which has collected in the venous systems is brought 
back again into the arterial systems. The contraction of the vessels 
of the intestines and liver forces out the blood collected there, so 
that the vessels in other organs — e.g., the kidney, brain, and peripheral 
parts of the body — are better filled, and the abnormal distribution 
of the blood is replaced by a normal one. 

[As first shown clinically by McKenzie and as emphasized by all the more 
recent careful studies of the effects of digitalis in patients with cardiac disease, 
the action of digitalis in lessening or abolishing the conductivity of the bundle 
of His (pages 266 and 294) is the most decisively beneficial effect produced by 
it in a large group of cases. It is this power of protecting the ventricle from a 
constant shower of stimuli arising in the fibrillating auricle, which is chiefly 
responsible for the almost miraculously curative action of the drug in many cases 
of threatening failure of the circulation.— Tr.] 

BIBLIOGRAPHY 

Bock: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 158. 

Bohm: Pfliiger's Arch., 1872, vol. 5, p. 153. 

Eychmiiller: Berl. klin. Woch., 1909, No. 37. 

Fahrenkamp: Heidelberg, unpublished experiments. 

Frank: Ztschr. f. Biol., 1901, vol. 41, p. 1. 

Fninkel : Miinchn. med. Woch., 1905, No. 32. 

Friinkel u. Schwartz: Arch. f. exp. path. u. Pharm., 1907, vol. 57, p. 79. 

Gottlieb: Medizinische Klinik, 1906, No. 37, p. 955. 

Griitzner: Arch. f. Psvchiatrie, 1906, vol. 42, p. 1, and Deut. Arch. f. klin. Med., 

1907, vol. S9, p. 131. 
Hasebroek: Ztschr. f. klin. Med., 1903, vol. 77. 
v. Hofmann: Pfliiger's Arch., 1901, vol. 84, p. 130. 
Lang u. Manswetowa: Arch. f. klin. Med., 1908, vol. 94, p. 455. 
Loewi u. Jonescu: Arch. f. exp. Path. u. Pharm., 1908, vol. 59, p. 71. 
Magnus u. Sowton: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 255. 
Midler, Otfried: Verb. d. 26. Kongr. f. innere Med., Wiesbaden, 1909. 
Sahli: Verb. d. 21. Kongr. f. innere Med., Berlin, 1901. 
Tigerstedt, K.: Skand. Arch. f. Physiol., 1907, vol. 20, p. 115. 
Vagt: Med. Klinik, 1909. 



CLINICAL ASPECTS OF DIGITALIS 301 

PRACTICAL EMPLOYMENT OF DIGITALIS 
Digitalis leaves were formerly used in England as a liousehold 
remedy for dropsy, but had been forgotten when Withering, in the 
last half of the eighteenth century, recognized their great value, and, 
after using them for a decade, published his results. As has long 
been known by clinicians, though only comparatively recently defi- 
nitely demonstrated by physiological assay, the pharmacological activ- 
ity of the leaves is very variable, and differs with' the locality from 
which they have been obtained, the age of the plants, and the time 
elapsed since they have been gathered, as well as with the conditions 
under which they have been prepared and preserved. This variation 
in the activity of different digitalis preparations, the importance of 
which has only recently been recognized, is perhaps the chief reason 
why this drug, even after extensive use for 125 years, is not yet gener- 
ally administered according to generally recognized and fully estab- 
lished rules, but is ordinarily employed by the individual physician 
according to his own subjective experience and impressions. Prepara- 
tions assayed by physiological tests are now obtainable and widely used. 
Active Principles. — Among the definitely constituted active prin- 
ciples of the digitalis leaves are the almost insoluble crystalline 
digit oxin, first prepared by Schmiedeberg (the digitaline nativelle 
of the French), and the rather insoluble digit alin of Schmiedeberg 
and Kiliani. In addition, digitalis leaves contain water-soluble gluco- 
sides named, by Schmiedeberg, digitaleins. All these substances possess 
typical digitalis actions, digitoxin being the most active and powerful. 
In the leaves they probably occur chiefly in the form of combinations 
with the tannic acid, which in pure form are insoluble in water but are 
readily soluble in dilute alkalies. 

In addition to these useful pure principles, there are also present a number 
of digitomm, which are saponins and do not possess the physiological actions of 
the digitalis bodies. On account of their local irritating actions, they often 
play a part in the causation of digestive disturbances which not infrequently 
develop in the therapeutic use of digitalis. [They also probably aid in bringing 
the insoluble and useful active principle into solution, as, for example, in the 
infusion. — Tr. ] 

Itii/alm is a proprietary preparation of the active principles dissolved in 
water and glycerin. According to Cloetta, it contains a soluble digitoxin, but 
according to Kiliani only an impure digitalein. [Hatcher has shown that the 
claims made for the activity of this preparation are greatly exaggerated, its 
Btrengtfa being only that of a standard tincture In laboratory tests made by 
the translator, this preparation has been found to be of inconstant strength, 
probably on account of deterioration on keeping for any length of time. — Tr.] 

Methods op Assay. — The digitoxin contents of digitalis leaves 
may be determined chemically, but it does not run parallel with the 
physiological activity of the leaves, for the loaves are much more 
active than can be accounted for by the digitoxin present (Zi( g< ribi in, 
Focke). As the other active principles cannot be estimated by 
chemical methods, physiological methods arc the only ones available 



302 PHARMACOLOGY OF CIRCULATION 

for the determination of the activity of the leaves or the galenic prep- 
arations made from them. 

Necessity of Assay. — The determination of physiological activity of these 
drugs is necessary because it varies so greatly in different specimens and in the 
different preparations made from them. Ziegenbein found differences of 100-200 
per cent, in the activity of the leaves gathered the same year but coming from 
different localities. Of still greater significance is the deterioration which takes 
place in the course of a year in leaves preserved according to the directions given 
by the pharmacopoeia (Focke). At times this amounts to a loss of 25 per cent, 
of their activity. It is thus easy to understand the great variations in the 
activity of different galenic preparations which with the tincture may amount to 
as much as 400 per cent. (Frankel 1 ) . There consequently is no other drug where 
it is more important to substitute for preparations of uncertain therapeutic 
activity those of known efficiency or pure substances of constant composition. 
Only thus can the therapeutic use of the drug become more accurate. [Xot only 
the loaves but also the galenic preparations deteriorate on keeping. As is widely 
known, this is especially true of the infusion, which deteriorates with such rapid- 
ity that it should be used only when freshly prepared. The fluidextracts appear 
to deteriorate but slowly. The translator found a deterioration of but 30 per cent, 
in a fluidextract which had been kept for three years in his laboratory. — Tr.] 

The physiological assay of digitalis and its preparations may be 
made with sufficient accuracy for practical purposes by determining 
the minimal dose which stops the heart in systole 35-40 minutes after 
injection into the lymph-sac of the frog (R. temporaria) . 

Employment of their pure active principles would be another way 
to secure exact dosage for the drugs of this group, which, besides the 
active principles present in the digitalis leaves, includes a number of 
substances, chiefly glucosides, derived from different sources. From 
a practical point of view the different strophanthins are the most 
important of these. 

Of these there are at least two known and well characterized, — one known 
as Strophanthin Bull ringer, or Strophanthin Merck, which is amorphous and is 
derived from Strophanthus kombe or Str. hispidus. The other, G-Strophanthin * 

(Str. Thorns), is crystallizable and is obtained from Str. gratus. These strophan- 
thins are readily soluble in water, as are convallamarin (from Convallaria 
majalis), hcUeborein (from the different species of Hellebore), adonidin (from 
Adonis vernalis), and the alkaloid erythrophlein. Strophanthin has proved espe- 
cially suitable for intravenous administration. The other substances named have 
thus far acquired no particular practical importance. 

A number of other glucosides of the digitalis group are present in various 
arrow-poisons, but they possess chiefly a toxicological interest. Such are, for 
example, echuyin (from a West African arrow-poison, antiarin (from Antiaris 
toxicaria), and euonymotoxin (from Euonymus atropurpureus) . A non-crystal- 
lizable glucoside with digitalis actions, scillain, is the active principle of squills 

(from Scilla maritima), a drug formerly much employed. 

Differences in the Actions of Different Digitalis Bodies. — 
The pharmacological actions of these different pure principles are 
by no means identical, for, although they all act on the same elements 
in the various organs, — i.e., have the same seats of action, and exert 
a qualitatively similar pharmacological action, — more refined pharma- 
cological analysis has shown many rather important quantitative 

* [Ouabain is synonymous with G. Strophanthin. — Tr.] 



CLINICAL ASPECTS OF DIGITALIS 303 

differences, not only in their actions on the cardiac muscle and 
ganglia, but also in their vasomotor actions, these being more pro- 
nounced, — for example, with digitoxin than with the others (Gottlieb 
u. Magnus) . The power of slowing the heart is another action which 
is possessed in varying degrees by various members of this group 
(Kochmann). 

Of greater practical importance are the differences manifested as 
regards the local irritant action in the stomach, and, above all, in 
connection with their absorbability and their excretion. In this last- 
mentioned connection the soluble strophanthins and the insoluble 
digitoxin are especially contrasted. In general, those substances 
which are soluble in water act more promptly than those which are 
insoluble in water. 

Cumulative Properties. — The different members of this group also 
differ from one another in respect to their so-called cumulative actions, 
although all of them exhibit the peculiar pharmacological behavior 
that, once their effects have been obtained, the effects persist for a 
considerable time. Obviously these substances are stored up in the 
heart. The degree and duration of their action depend on the amount 
thus stored up, the relatively long-continued action of single doses 
being explained by the fact that, once this combination of the drug 
with some as yet undetermined elements in the heart has taken place, 
it is but slowly broken up again. By continued administration of 
new doses the heart continues to absorb larger and larger amounts, 
and, as a result of the continued absorption, in the course of several 
days the physiological action may be developed to the desired degree. 

"With all the drugs of this group, still further administration 
may lead to a so-called cumulation, due to an accumulation of the 
drug in the heart in amounts larger than is desired. The persistence 
of the action is quite independent of the rapidity with which it 
develops, for a fairly lasting effect may be obtained immediately 
after the intravenous injection of an efficient dose of strophanthm, 
or much later by the oral administration of digitalis leaves, which 
ordinarily produce the typical effects on the circulation only after 
24 hours, or even much later. However, the different digitalis bodies 
show marked differences in the degree and intensity of this lasting 
action, and these are of decisive importance for the occurrence of 
cumulation, as this depends on the summation of the actions of new 
doses with the persisting actions of the earlier ones. 

The syrnptoms of cumulation are similar to those resulting from 
the administration of single toxic doses. The first are usually nausea, 
vomiting, and diarrhoea, succeeded in more pronounced cases by 
alarming retardation and arrhythmia of the pulse. The sudden change 
from a slow to a rapid pulse seen in animals poisoned by digitalis 
may occur, but not necessarily so even in most severe poisoning in 
man. 



304 PHARMACOLOGY OF CIRCULATION 

The vomiting, which occurs in cumulation, is a symptom produced 
by the drug after absorption, and is not to be confounded with that 
due to local irritation of the stomach, which often occurs in susceptible 
individuals after the first doses of digitalis bodies. This local irritation 
in the alimentary canal is caused not only by the useful active princi- 
ples but also by the digitonins, the saponin-like constituents of the 
digitalis leaves. 

Differences in Liability to Cause Cumulation. — Comparative in- 
vestigations in animals have shown that the circulatory effect develops 
a few hours after the subcutaneous injection of strophanthin, while 
after injection of digitalis or digitoxin a much longer period elapses. 
On the other hand, the effects of strophanthin last a much shorter 
time than those of digitalis or digitoxin. The effects of this last- 
named glucoside are especially persistent, so that the interval between 
doses must be longer when it is used, if cumulative effects are to be 
avoided (Frdnkel 2 ) . Digalen (see p. 301) also has a well-developed 
cumulative action (Frankel 3 ). This property of causing cumulative 
effect is, however, necessarily present in any drug possessing the typi- 
cal digitalis actions and is essential for securing the desirable lasting 
therapeutic effects. Therefore, cumulative action may always result 
from continued administration of any member of this group. 

Principles Governing the Dosage and Choice of Preparation. — 
In the clinical employment of digitalis, the attempt should be made to 
administer doses only large enough to secure the necessary lasting 
effects without causing the symptoms of cumulation to appear. The 
use of physiologically assayed preparations is the best means of accom- 
plishing this. [Very frequently, however, as emphasized by Mc- 
Kenzie, the desired effect on the heart may be obtained only by 
d'oses which also cause nausea and vomiting. The danger from the 
cumulative action of digitalis has been generally over-emphasized by 
pharmacologists and by many clinicians. — Tr. ] 

The employment of the pure active principles has thus far not been 
widely favored in Germany, but in France digitoxin is much employed, 
in spite of its pronounced tendency to cause cumulative effects (Marx, 
Zeltner) . Digitalin would appear to possess insufficient physiological 
activity for practical therapeutic administration. [Probably because 
usually used in too small doses. — Tr.] Besides this, it is decomposed 
in the stomach to a considerable and indeterminable extent (Deucher). 
Although the strophanthins are so efficient when administered intra- 
venously, they are but moderately active and the effects produced by 
them are not lasting when they are administered by mouth. [This is 
perhaps in part due to the fact that, they are excreted by the kidney 
more rapidly than they are absorbed from the alimentary canal. — Tr.] 

The curative effects obtained by the use of digitalis are the result 
of the combined actions of the various substances contained in the 
leaves. As these substances exhibit marked differences from one 



CLINICAL ASPECTS OF DIGITALIS 305 

another in the character of their actions, in their rates of absorption, 
and in the persistence of their actions, it is very possible that the 
advantages claimed for the leaves or their preparations are due to 
their containing this combination of substances. Until these conditions 
are more thoroughly comprehended from a pharmacological point of 
view, it is, as a rule, therapeutically correct to give preference to the 
oral administration of the leaves or their galenic preparations. 

The dosage of digitalis leaves and of their galenic preparations 
varies with the length of time that the drug is to be administered. The 
total amount administered during the whole treatment is much 
more important than the size of the individual doses. This is so 
because of the slow absorption of the active principles and their 
accumulation in the heart, as well as because of their characteristic 
power to produce somewhat lasting effects. (Maximal dose 0.2 gm., 
1.0 gm. per diem.) As a general rule, three or four doses of 0.1 gm. 
each of a good active digitalis powder per diem may be given, and such 
administration may be persisted in for three or four days, but in 
such dosage not for a longer period. [Much larger doses, such as 
4.0-8.0 c.c. of the tincture, may be given every 24 hours for several 
days without danger, if the patient is kept quiet and under careful 
observation. In fact, at times it is only by the use of such doses, 
or even larger ones, that the desired beneficial actions may be 
obtained. — Tr.] 

If the full therapeutic effect is obtained on the second or third 
day, most competent authorities advise its discontinuation for a time 
or a diminution of the daily dose. In this way the cumulative action 
is most surely avoided. Other observers believe that the good effects 
of a digitalis cure are more lasting if the administration be con- 
tinued, even after the appearance of the desired actions, until from 2.0 
to 2.5 gm. in all have been taken. Others advise the continued 
administration of smaller doses, about 0.1 gm. per diem, which can be 
taken for a long time without the development of cumulation. [As a 
matter of fact, the dose for each case must be determined by trial. — 
Tr.] 

The infusion of digitalis is preferred by many physicians, but is 
very unstable (Loewi) and is weaker and more uncertain in its action, 
because, according to the care with which it is prepared, varying por- 
tions of the active principles may be extracted from the leaves. On 
the other hand, it is claimed that the infusion is less likely directly 
to irritate the stomach, perhaps because it contains only a smaller 
amount of the active principles, but also perhaps because fewer of the 
contaminating substances are extracted from the leaves. Similar 
advantages may be possessed by other extracts, — for example, the 
quite stable dialysate, — as well as by the tincture, which is so often 
preferred for long-continued use. 
20 



306 PHARMACOLOGY OF CIRCULATION 

Digipu ration. — During the preparation of digipuratum, an extract 
of purified digitalis, the elimination of inactive contaminating sub- 
stances is carried still further, for as much as 90 per cent, of the 
solid constituents may be removed from alcoholic extracts of the 
leaves without diminishing their physiological or therapeutic activity. 
It would appear that this preparation is especially free from digitonin 
and other saponin-like components of the crude drug, for it represents 
in almost pure form the combinations of tannic acid and the active 
glucosides. These are insoluble in the stomach, and therefore irritate 
its mucous membrane but slightly, while, in the alkaline intestinal 
contents, they are readily soluble, and therefore relatively easily 
absorbed. According to some observers (Hopffner), this preparation 
disturbs the stomach less than all other digitalis preparations of equal 
physiological activity.* ,. 

Intravenous Administration. — When in critical cases it is im- 
portant to obtain the effect cf digitalis more ramdly than is possible 
by oral administration, intravenous administration may, with great 
advantage, be employed. The subcutaneous or intramuscular injection 
of all active digitalis preparations is painful, and, if really effective 
doses are thus administered, marked local irritation results, while the 
subcutaneous injections of weaker preparations or of relatively high 
dilutions possess no advantage over their administration by mouth 
[except that at times the stomach rejects all medication administered 
orally. In such cases the rectal administration of relatively large 
doses in moderate dilution may be followed by gratifying results. — 
Tr.]. 

After intravenous injection of suitable preparations of digitalis, 
the effects on the circulation may manifest themselves within a few 
minutes, and the favorable action is usually fully developed at the 
end of an hour and often lasts for a long time [12 to 24 hours or 
more. — Tr.]. Only pure substances readily soluble in water should 
be used for this purpose. This method was first employed by Kott- 
mann, who used digalen for this purpose, but, since its recommen- 
dation by Frdnkel and Schwartz, strophanthin in dosage of 0.5-1.0 

* [Inasmuch as both clinical experience and such laboratory investigations 
as those of Hatcher have clearly demonstrated that the nausea and vomiting 
produced by digitalis is usually the result of its action on the vomiting centres, 
and as the desired effects on the circulation often manifest themselves only with 
doses which also produce these undesirable effects, one must accept with extreme 
caution the claims made for any preparation of digitalis or any of its group 
that it does not cause gastric disturbances. Ordinarily this is equivalent to 
stating that the preparation is more or less inert in other particulars. The 
claimed superiority of digipuratum in this respect may appear to be justified 
by clinical observation, but the translator has seen it cause typical digitalis 
vomiting. If this drug is really less likely to upset the stomach when given in 
therapeutic doses, it is perhaps due to the convenience with which sufficient 
amounts may be given without causing the patient to swallow nauseous tasting 
mixtures or draughts. — Tr.] 



TREATMENT OF CIRCULATORY FAILURE 307 

mg. has proved an important advance in therapeutics.* [Cushny and 
Dock over ten years ago injected a dilute solution of digitalis into 
the vein of a human patient, with temporary good results. — Personal 
communication to translator.] 

BIBLIOGRAPHY 

Boos: Archiv of Internal Medicine, 1911, No. 4. 
Cloetta: Munchn. med. Woeh., 1904, No. 33, p. 1466. 
Deueher: Arch. f. klin. Med., 1896, vol. 62. 
Focke: Arch. f. Pharm., 1903, vol. 241, p. 669. 
Focke: Therap. d. Gegenwart, June, 1904. 

1 Frankel : Therap. d. Gegenwart, March, 1902. 

2 Frankel: Arch. f. exp. Path. u. Pharm., 1903, vol. 51, p. 84; 1907, vol. 57, p. 123. 

3 Frankel: Ergebnisse d. inn. Med., 1908, vol. 1, p. 68. 
Frankel u. Schwartz: Arch. f. Path. u. Pharm., 1906, vol. 57. 
Gottlieb u. Tambach: Miinchn. med. Woch., 1911, No. 1. 

Gottlieb u. Magnus: Arch. f. exp. Path. u. Pharrr., 1901, vol. 47, p. 135. 

Hopffner: Munchn. med. Woch., 190S, No. 34. 

Kiliani: Miinchn. med. Woch., 1907, No. 18. 

Kochmann: Arch, inter, de Pharmacodyn. et'de "Hierap., 1906, vol. 16, p. 221. 

Kottmann: Ztschr. f. klin. ? led., 1905, vol. 56. 

Loewi : Wien. klin. Woch., 1906, No. 39. 

Marx: Inaug. Diss., Strassburg, 1898. 

Miiller, Leo: Munchn. med. Woch., 1908, No. 51. 

Schmiedeberg: Arch. f. exp. Path. u. Pharm., 1874, vol. 3, p. 16. 

Zeltner: Miinchn. med. Woch., 1900, No. 26. 

Ziegenbein: Arch. f. Pharm., 1902, vol. 240, No. G, p. 454. 

TREATMENT OF CARDIAC AND VASCULAR DEPRESSION 

By cardiac weakness is understood a disturbance of the circulation 
which is characterized by weak, rapid, and often irregular pulse, 
pallor, and sometimes cyanosis. Such conditions may develop in the 
final stages of many kinds of poisoning as well as in the course of 
various infectious diseases. In an earlier section (p. 290) it has been 
stated that cardiac insufficiency, which is equally pronounced in both 
right and left hearts, results only in a slowing up of the blood flow 
without the occurrence of stasis. This would typify the conditions 
in a case of uncomplicated depression, but, as a matter of fact, 
except as a result of hemorrhage, cardiac weakness is never observed 
except in combination with a more or less general vasoparesis, for not 
only the toxins of infectious diseases, but also other cardiac depres- 
sants, such ;is chloral hydrate, chloroform, arsenic, etc., affect both 
the heart and the vasomotor centres [or the vessels themselves. — Tr.]. 

1 [II Bhould 1«' emph&Bized that strophanthin and ouabein are both enormously 
toxic substances. Since their introduction as drugs to be administered intra- 
venously, clinicians have learned thai their administration is not unattended 
with danger. 0.3 mg. is ordinarily a sufficient initial dose and, in the translator's 
opinion, 0.5 mg. is the largest amount that should be given as a first dose. 

Further, all those who have used these drugs at all extensively insist on the 
extreme danger of giving them to patients who have recently taken any con- 
siderable amounts of digitalis or its conveners. Two days or so should be 
allowed to elapse between the lasl considerable digitalis dosage .driven by mouth 
and the intravenous administration of strophanthin or ouabein. — Tr.] 



308 PHARMACOLOGY OF CIRCULATION 

Consequently, the phenomena resulting- from vasomotor depression 
develop simultaneously with those resulting from cardiac insufficiency, 
or precede or follow them. Moreover, even if the heart is not directly 
affected by the toxic agents, vasomotor depression being the primary' 
condition, cardiac weakness develops secondarily, for, as stated in the 
introductory portion of this chapter, the functions of the heart 
and of the vessels reciprocally affect each other most markedly. 

A vasoparesis in the splanchnic system produces the most severe 
disturbances of the circulation. Under normal conditions the vessels 
of the abdominal viscera are maintained in a state of moderate con- 
traction by the constantly acting influence of the vasomotor centres. 
If this influence be removed, the vessels dilate and become a reservoir 
of such great capacity that its filling deprives the other vascular sys- 
tems of most of their blood. At the start the organism compensates 
for this by the constriction of the vessels in other systems, and 
pallor, due to contraction of the vessels of the skin and muscles, 
appears before the general blood-pressure has sunk appreciably. From 
the teleological point of view, this regulating process appears useful, 
as thus the blood flow through the heart and nervous system is main- 
tained as long as possible, for when this fails the general blood- 
pressure must sink so decidedly that the insufficient blood flow in 
the nervous system causes faintness, while inadequate circulation 
through the cardiac muscle impairs its functional power. 

In man the symptoms of such collapse, due chiefly to vasoparesis, 
closely resemble those resulting from cardiac weakness. In both 
conditions the blood-pressure in the aorta falls, the pulse tension is 
lowered, and the pulse becomes rapid and small. This acceleration 
is due to the depression of the vagus tone, which, in turn, is a conse- 
quence of the lowered blood-pressure. In cardiac failure the pulse 
becomes feeble and small because the strength of the cardiac contrac- 
tions is primarily depressed; in vasoparesis the same changes occur 
because the heart contracts when insufficiently filled with blood. In 
primary cardiac depression the heart pumps insufficiently because of 
impairment of its power to contract, but in vascular paresis, even 
though the cardiac muscle is capable of vigorous contractions, so little 
blood is received by the heart that only insufficient amounts may be 
pumped out into the aorta. In each case the effect on the flow of 
Mood throughout the body is the same. It is therefore clear that 
cardiac weakness and vascular depression may not readily be differ- 
entiated by their symptoms and that they usually exist coincidently. 

Theoretically they differ from each other in that in conditions of vaso- 
paresis the great veins of the systemic circulation are insufficiently filled, while 
in primary cardiac failure the blood accumulates largely in the veins of both the 
systemic and pulmonary circulations. It has, however, been stated previously 
that cardiac weakness accompanied by a slowing up of the blood flow causes 
merely an alteration in the blood distribution throughout the body and is very 
different from those forms of cardiac insufficiency for which stasis is character- 
istic. If in cases with disturbance of cardiac function stasis is not markedly 



TREATMENT OF CIRCULATORY FAILURE 309 

developed, there results merely a diminished flow of blood throughout the whole 
circulation, a relatively insufficient filling of the arteries, and a fall in aortic 
blood-pressure, just as is the case in conditions of vascular depression. 

Circulatory failure resulting from vasoparesis occurs in the ad- 
vanced stages of many toxic conditions, the vasomotor centres being 
often markedly depressed by a number of narcotic poisons while the 
heart is still beating well and the respiratory centre remains suffi- 
ciently excitable to maintain life. Although formerly in such cases 
of circulatory failure it was the custom to consider them as due to 
cardiac weakness, Romberg and his coworkers have correctly insisted 
that, in the course of infectious diseases, disturbances of the circu- 
lation develop which, closely resemble the picture seen in vasomotor 
paresis. Using pneumococci and diphtheria bacilli, as well as pyocya- 
neus cultures, they were able to show experimentally that, at any rate 
during a long period during which the blood-pressure continued to fall, 
this was chiefly due to a vasoparesis and not to any direct harmful 
action on the heart (Romberg, Passler, Bruhns u. Muller, Passler u. 
Roily), and that the same holds true for experimentally induced 
septic peritonitis (Romberg u. Heinecke) . 

In man also the collapse occurring in such conditions may in 
most cases be attributed chiefly to the central vasodepressant action 
of the bacterial toxins. However, Krehl claims that usually, when the 
disease is at its height, the heart, too, has been harmfully affected, and 
that this is not simply a secondary effect of the vasoparesis but a 
direct effect resulting from the action of the toxins on the heart itself. 
It has been proved, especially for experimental diphtheria intoxication, 
that in the more advanced stages a progressive true cardiac depression 
is superimposed on the depression of the vasoconstrictor centres 
{Roily, SteysJcal). Other poisons causing depression of the nerve- 
centres produce the same effects, lessened reflexes, depression of the 
vasomotor and respiratory centres, all occurring together in such 
poisoning as that induced by chloral hydrate. In healthy animals 
the heart is less affected by this drug than are the vital centres in 
the medulla. The diseased heart, however, is much less resistant, so 
that in chloral poisoning, if the heart be already diseased, death may 
result from cessation of the heart's action before the respiration 
fails completely. It would appear that diphtheria toxin may act 
similarly (Gottlieb). 

It was, therefore, of the highest clinical importance to obtain, by 
closer investigation of cases of circulatory failure, new criteria for 
determining in the individual case whether the damage done to the 
heart by the toxins of the infection or the vascular depression caused 
l>y them is of greater moment, for the choice of the means used for 
tiv;ifing the condition must be made according to the conclusion 
reached. Willi these conditions and farts in mind, Passler, using 
infected animals, i n vest ign ted Hie effect of various cardiac and vascu- 



310 PHARMACOLOGY OF CIRCULATION 

lar drugs in the final stages of the toxtemia, and Schwartz did the 
same for the earlier stages. It is clear, however, that the interpretation 
of their experiments is attended by great difficulties, for, in the first 
place, the pathological conditions on which the drugs acted were not 
sufficiently understood, and, secondly, most drugs affecting the func- 
tion of the heart also act on the vessels and vice versa. 

In cases in which cardiac insufficiency is the predominant 

FEATURE, 

Digitalis is the first drug to be thought of, but the slow absorption 
of digitalis makes it self-evident that in acute circulatory failure not 
much can be expected from its oral administration. The intravenous 
injection of strophanthin is, however, a feasible procedure from which 
good results might be expected, as the injections are so promptly fol- 
lowed by the full development of its actions, and, as a matter of fact, 
it has been found clinically that an increase of the volume of the pulse 
and a rise in blood-pressure often follow the intravenous injection of 
0.5 mg. of strophanthin in the collapse of typhoid and that of other 
conditions. [Crile's experiments with the intravenous injection of 
digitalis in animals suffering from shock would indicate that in 
collapse of this type strophanthin would be of no value, or would 
act harmfully. — Tr.] 

Camphor may also improve the action of the failing heart. It is 
used for this indication in doses of 0.1-0.5 gm. dissolved in oil, or in 
oil and ether, or in ether and alcohol ; but, on account of its insolu- 
bility, it is but slowly and uncertainly absorbed from the stomach. 
By reason of its volatility and its solubility in the lipoids of the 
tissues, amounts sufficient to produce effects on the circulation are 
quite readily absorbed from the subcutaneous tissues [see p. 316 — Tr.] , 
but its action is rather evanescent, for in the body it is transformed 
into camphor-glycuronic acid (Schmeideberg) . 

Other Actions. — In connection with the general systemic action of camphor 
the stimulant action on the cerebral function should again be mentioned 
(p. 24). In animals large doses cause clonic convulsions, but these have been 
very rarely observed in man, as the margin between therapeutic and toxic doses 
is so great. The respiratory and vasomotor centres are stimulated, and increased 
blood flow in the skin causes, even after small doses, a subjective feeling of 
warmth. Very large doses produce an antipyretic effect in fever. [Its local car- 
minative action on the stomach, with the usual reflex effect, should also be 
mentioned. Moderate antiseptic powers are also possessed by this drug. — Tr.] 

BIBLIOGRAPHY 

Gottlieb: Med. Klin., 1905, No. 25. 

Hopffner: Deut. Arch. f. klin. Med., 1908, vol. 92, p, 485. 

Krehl: Pathol. Physiol., Leipzig, 1907, 5th edition, p. 119. 

Liebermeister: Medizin. Klinik, 1908, No. 8. 

Ortner: Prag. Ztschr. f. Heilk., 1905, p. 183. 

Passler: Deut. Arch. f. klin. Med., 1S99, vol. G4, p. 715. 

Passler u. Roily: Deut. Arch. f. klin. Med., vol. 77, p. 96. 

Roily: Arch. f. exp. Path. u. Pharm., 1S99, vol. 42, p. 283. 

Romberg u. Heinecke: Deut. Arch. f. klin. Med., 1901, vol. 69, p. 429. 



TREATMENT OF CIRCULATORY FAILURE 311 

Romberg, Passler, Bruhns u. Miiller: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 652. 
Sehmiedeberg u. Hans Meyer: Ztschr. f. physiol. Chemie, 1879, vol. 3, p. 422. 
Schwartz: Arch. f. exp. Path. u. Pharm., 1905, vol. 54, p. 135. 
Steyskal: Ztschr. f. klin. Med., 1902, vol. 367; vol. 51, p. 129. 

In conditions of uncomplicated vascular depression no benefit 
can be expected from the administration of cardiac stimulants, for 
such can result only if the tone of the splanchnic vessels be restored. 
If this be done, the previously insufficient blood flow through the 
vessels of the skin, muscles, and brain becomes sufficient (v. Basch, 
Biedl), and, the heart again receiving sufficient amounts of blood, 
the pressure in the aorta rises. It is thus that sensory reflexes and 
centrally acting vasomotor stimulants — for example, strychnine and 
caffeine — may favorably influence vascular paresis. On the other 
hand, peripherally acting vasoconstricting drugs, such as epinephrin, 
may similarly alter the general distribution of the blood in spite of 
the existing depression of the vasomotor centres. 

Sensory Stimuli. — As a general rule, it may be stated that a very 
strong sensory stimulation reflexly lowers the blood-pressure, while 
weaker stimuli raise it. The effects resulting from the use of mus- 
tard plasters and baths or of friction with skin irritants, etc., are best 
explained as resulting from such reflex actions. By the use of the 
plethysmograph it may be shown that the kidney volume diminishes 
while the blood-vessels are more completely filled and the blood- 
pressure rises under the influence of such sensory stimulation (Wer- 
theimcr, Boy). 

Strychnine is the best example of a central vasomotor stimulant, 
its action on the circulation being a partial expression of its action on 
the central nervous system. Therapeutically it is of importance that 
the action on the vasomotor centres develops before the occurrence of 
the convulsive symptoms. In this stage mild sensory stimuli, such 
as blowing on the skin, reflexly cause a rise in blood-pressure in the 
rabbit. However, a persistent rise in the blood-pressure occurs in nor- 
mal animals only when the increased reflex excitability of the motor 
ferities of the cord is fairly evident (Denis). With depressed ex- 
citability of the central nervous system, the danger of causing convul- 
sions is much lessened, and it has been shown that strychnine may 
improve the circulation in chloralized animals Avithout necessarily 
causing convulsions. These actions are the basis for the adminis- 
tration of this drug in acute alcohol or chloral poisoning, as also in 
other conditions with similar disturbances of the circulation, a prac- 
tice much more common in other countries than in Germany.* In 
England and America a direct favorable action on the tone of the 
heart muscle is attributed to strychnine, and recent experiments of 
Cameron indicate that this is the case. 

* [Many careful clinicians as a result of painstaking investigation of the 
effects of Btrychnine under such conditions have lost their faith in this drug as 
a mi miis of improving the circulation in infectious disease. — Tit.] 



312 PHARMACOLOGY OF CIRCULATION 

BIBLIOGRAPHY 

v. Basch: Ber. d. Sachs. Akad. d. Wiss., 1875, vol. 27, p. 373. 

Cameron, cited from Hirschf elder : Diseases of the Heart and Aorta, Philadelphia 

and London, 1910, p. 181. 
Denis: Arch. f. exp. Path, u- Pharm., 18S5, vol. 20, p. 306. 
Biedl u. Rainer: Pniiger's Arch., 1900, vol. 79. 
Roy and Sherrington: Journ. of Physiol., 1890, vol. 11, p. 85. 
Wertheimer: Arch, de Physiol., 1893, No. 2. 

Caffeine. — The less dangerous caffeine resembles strychnine in its 
action on the circulation, but never increases the blood-pressure to so 
great an extent. In previous sections it has been shown that caffeine 
also is a stimulant for the whole central nervous system (p. 25ff), its 
vasomotor actions going hand in hand with the stimulation of the 
respiratory centre and of the cerebral function. In this way is ex- 
plained the fact that caffeine is one of the most useful analeptics 
in cases where the circulatory failure results from depression of all 
the functions of the central nervous system. 

Experimentally it has been shown that the vasomotor excitability in dogs 
poisoned by alcohol is increased under the influence of caffeine and that the 
blood-pressure returns to a normal height after moderate doses {Binz). This 
return of reflex excitability may also be well observed in chloralized rabbits, 
Passlcr studied the actions of caffeine on the depressed circulation of infected 
rabbits, and found that subcutaneous injections of caffeine-sodium salicylate 
raised the lowered blood-pressure even in the final stages of pronounced vasomotor 
depression. Under these conditions the reflex excitability of the vasomotor 
centres was restored or improved, and this favorable action persisted for a con- 
siderable time — up to Hi- hours. 

In experiments on animals it may be shown that it is especially 
moderate doses of caffeine which favorably influence the blood-pres- 
sure, an increase of the dose causing further rise, and very large 
doses or rapid intravenous injection being followed by a fall. This is 
due to the depression of the functional power of the heart which 
undoubtedly occurs after toxic doses of caffeine. The discussion of the 
cardiac action of caffeine (see pp. 267-8) has made it evident that under 
normal conditions it produces no favorable effects on the performance 
of the heart, and that after large doses there is a diminution of the 
amount of blood expelled by the heart in the unit of time. This should 
soon result in a fall of the arterial pressure, but actually this remains 
high, as a result of the opposing influence of the vasoconstriction 
caused by the drug (Bock). Thus, during the action of caffeine we 
must assume that increased tone of the splanchnic vessels occurs 
simultaneously with lessening of the heart's pumping capacity. 

Further, as has been previously mentioned, caffeine exerts two 
actions, each of which tends to affect the frequency of the pulse in 
opposite directions. On the one hand, it stimulates the vagus centre 
and slows the pulse (Wagner, Sivirski, Bock), and this effect appears 
to be the predominant one resulting from therapeutic doses in man 
(Riegel) [?Tr.]. Following larger doses, on the other hand, the 



TREATMENT OF CIRCULATORY FAILURE 313 

pulse is always accelerated, as a result of stimulation of the accelerator 
terminations in the heart. It is possible that this action on the 
motor centres in the heart plays a more important role in patho- 
logical conditions.* From what has been said, an increase in the 
blood-pressure following the administration of caffeine is to be attrib- 
uted to the vasoconstriction in the splanchnic system as well as to an 
increased frequency of the pulse in the later stages of its action. 

Therapeutically this power of bringing about an alteration in the 
distribution of the blood is made use of in conditions of vascular 
depression. It is possible, too, that this forcing of the blood out of 
the visceral vessels, as well as direct stimulation of the cerebral func- 
tion, accounts for the use of the various beverages containing caffeine. 
The effect of caffeine in overcoming the feeling of fatigue after eating 
may be due to the action of caffeine in preventing the hyperemia of 
the intestinal vessels which usually follows the ingestion of large 
amounts of food, and thus preventing the relative anaemia of the 
brain which accompanies hyperemia of the portal system. The in- 
creased blood supply to the skin expresses itself as a subjective feeling 
of warmth following the drinking of beverages containing caffeine. 

The indirect effect on the heart resulting from the rise in blood- 
pressure due to central vasoconstrictor stimulation is of much im- 
portance, for under the influence of caffeine the constriction of the 
visceral vessels brings larger amounts of blood to the right heart, 
and as a result an improvement of the cardiac function occurs. This 
is quite different from the effects in the heart-lung circulation {Bock, 
Tiering), where the systemic vessels have been eliminated and there- 
fore can exert no influence on the circulation. [This favorable effect 
on the cardiac function is still further augmented by the peripherally 
induced dilatation of the coronary vessels. — Te.J Santesson has in 
indisputable fashion experimentally demonstrated an indirect im- 
provement of the cardiac function due to this factor. It is probable 
that in pathological conditions the increase of the absolute power 
of the heart, — i.e., its ability to overcome a greater resistance — is of 
importance. A weaker heart could thus better meet the demands 
which an increase of the blood-pressure makes upon its contractile 
energy. 

The soluble double salts, caffeine-sodium benzoate and caffeine- 
sodium salicylate, are used as circulatory stimulants in preference to 
the pure caffeine, and are advantageously administered subcutanoously 
in doses of 0.2-0.5 gm., a dosage about twice as large as that of pure 
caffeine. Strong black coffee is also much used in conditions of col- 
lapse, in narcotic poisoning, and in cases of threatening cardiac 
weaknoss, < tc. 

* [Tn Hii* connection the render [a reminded <>f caffeine's power of causing 
or augmenting extrasystoles (p. 2(J8). — Ta.] 



314 PHARMACOLOGY OF CIRCULATION 

Pure caffeine (or theine) occurs as silky shining needles of somewhat bitter 
taste. It is soluble in water in the proportion of 1 : 50, much more soluble in 
hot water and in alcohol. It is soluble in G parts of chloroform, by the use of 
which solvent it may be extracted from the crude drugs. Its chemical composition 
is that of a trimethylxanthine. Theobromine and theophyllin, which are dimethyl- 
xanthines, pharmacologically closely resembling it, are discussed elsewhere 
(see p. 364). 

In all parts of the earth, plants in which these substances occur are used 
for beverages or as stimulants. A cup of coffee prepared from 1G grammes of 
roasted beans contains about 0.1-0.12 gm. of caffeine. The same amount, with 
some theophyllin, is contained in an infusion made from 5-6 gm. of dried tea 
leaves. Kola nuts (Kola acuminata) come from Africa, while cocoa, which con- 
tains theobromine, Paraguay tea (Ilex paraguayensis), and guarana paste (Paul- 
linia sorbilis), which contains especially large amounts of caffeine and which 
has been much used for the relief of headaches, all come from America. 

Other Constituents of Tea and Coffee. — Besides caffeine, by all 
means the most important factor in producing their effects, the dif- 
ferent beverages and stimulants of this group contain other substances 
which also contribute to their general effects. In coffee, substances 
with aromatic odor, formed during the roasting from legumin, sugar, 
and resins, and in tea, ethereal oils contained in the leaves, are of 
some physiological significance. These beverages owe their character- 
istic odor and taste to the presence of these substances, which also 
exert some action on the central nervous system, causing an increase 
in the frequency of respirations, muscular restlessness, and distinct 
psychic stimulation. The so-called caffeine-free coffee, from which 
about two-thirds of the caffeine has been removed by extraction with 
benzol, preserves its pleasant flavor while the stimulating effects 
on the nervous system are largely lacking (Harnack). 

Other Actions. — In connection with the general picture of the 
caffeine action the reader is referred to the action on the cerebral 
function (p. 25 ff.), on the respiration (p. 335), on the renal function 
(p. 360 ff.), and on that of the muscles. Its effects on the body temper- 
ature are of some interest, after moderately large doses the temperature 
sometimes rising 0.5° C. and after toxic doses more than 1° C. 

Acute poisoning by caffeine has been observed by investigators who 
intentionally poisoned themselves and after immoderate drinking of 
beverages containing caffeine. Conditions of tipsy excitement, sleep- 
lessness, vertigo, and muscular tremors, as well as nausea and diar- 
rhoea, or pronounced frequency of micturition, may result from injec- 
tion of 0.5-0.6 gm. After injection of larger doses of about 1.0 gm., 
in addition to these symptoms, palpitation and irregularity of the 
heart,* and marked increase of the pulse frequency, with a feeling of 
anxiety and at times some of the symptoms of angina pectoris, may 
arise (Lehmann, Curschmann) . Usually the poisoning passes off 
gradually without any serious after effects. As much as 1.5 gm. has 
been taken by rather insusceptible individuals without serious results 
(v. Frerichs). 

* [Due to extrasystoles. — Tr.] 



TREATMENT OF CIRCULATORY FAILURE 315 

Only a small part of the caffeine administered is excreted un- 
changed in the urine (Bost) ; another portion appears in the urine, 
after a gradual splitting off of the methyl radicals, as monomethyl- 
xanthine and xanthine, but the largest portion is entirely decomposed 
in the body. The dimethylxanthines suffer a similar loss of their 
methyl radicals (Bondzynski, Albanese, Eriiger). 

BIBLIOGRAPHY 

Albanese: Arch. f. exp. Path. u. Pharm., 1S95, a^oI. 35, p. 449. 

Binz: Arch. f. exp. Path. u. Pharm., 1878, vol. 9, p. 31. 

Binz: Zentralbl. f. klin. Med., 1900, vol. 21, No. 47. 

Bock: Arch. f. exp. Path. u. Pharm., 1900, vol. 43, p. 367. 

Bondzynski u. Gottlieb: Ber. d. Chem. Ges., 1895, vol. 28. 

Curschmann: Deut. Klin., 1873, p. 377. 

Cushny u. van Naten: Arch, intern, de Pharmacodyn., 1901, vol. 9, p. 1C9. 

v. Frerichs: Wagner's Handworterbueh d. Phvsiol., Braunschweig, 1S53, vol. 3, 

p. 721. 
Harnack: Deut. med. Woch., 1908, No. 45. 

Kriiger u. Schmidt: Arch. f. exp. Path. u. Pharm., 1901, vol. 45, p. 259. 
Kriiger u. Schmidt: Ber. d. deut. Ges., 1899, vol. 32. 
Lehmann, K. B.: Arch. f. Hygiene, 1898, vol. 32, p. 310. 
Passler: Deut. Arch. f. klin* Med., vol. 64, p. 715. 
Riegel: Kongr. f. inn. Med., 1884. 

Post: Arch. f. exp. Path. u. Pharm., 1895, vol. 36, p. 56. 
Santesson: Skand. Arch. f. Phvsiol., 1901, vol. 12, p. 259. 
Swirski: Pfliiger's Arch., 1904,' vol. 103. 
Wagner: Diss., Berlin, 1885. 

Camphor is another drug used for its effects on the arteries. 
On page 274 it has been stated that this drug brings about changes in 
the distribution of the blood and in the blood-pressure by stimulation 
of the vasomotor centres, but these effects are obtained in normal 
animals only by the administration of doses large enough to cause 
convulsions. In man, however, the doses usually are much smaller 
than those which cause convulsions, and yet it is certain that the 
subcutaneous injection of 0.1-0.4 gm. of camphor frequently improves 
the circulation, though often only temporarily, even when the patient 
is in extremis. In accordance with this are Passler 's observations of 
the distinct improvement of the vasomotor function which followed the 
injection of camphor in infected animals( ( ?) Translator 's note, p. 316). 

This suggests that perhaps camphor produces more marked effects 
on the functions of these centres when they are depressed than under 
normal r-onditions. It has often been observed that when the tone 
of the centres is diminished they react to smaller doses of stimulating 
substances than when they are functioning optimally, somewhat as a 
sf rin-- may be stretched by less power if its tension has been previously 
diminished. 

Thus far this fact, of equal practical and therapeutic importance, is not 
thoroughly understood. In a similar fashion the central innervation of muscular 
movements is distinctly Stimulated by alcohol <>r e:iHYinp if these he administered 
in conditions of fatigue [Frey, Joteyko), although the normal nuncio innervation 
is not measurably influenced by similar (loses, and the Bame is true of the action 



316 PHARMACOLOGY OF CIRCULATION 

of similar doses of alcohol on the respiratory centre (Wendelstadt ) . By such 
analogy it may, therefore, be possible to explain the fact that certain drugs 
improve the depressed function of the vasomotor centres, even though the optimal 
normal function is uninlluenced by equal doses. 

In addition, the results of stimulation of the vasomotor centres 
are much more apparent in pathological conditions of the circulation 
than in conditions of health, for moderate vasoconstriction causes in 
the healthy animal only an alteration in the distribution of the blood, 
and, on account of the normal compensatory regulations, the blood- 
pressure need not rise. If, on the other hand, in pathological con- 
ditions of the circulation this compensatory regulation is disturbed 
and the portal vessels dilated, these drugs stimulating the vasomotor 
centres cause constriction of the abdominal vessels and bring about a 
normal distribution of the blood once more, and thus the previously 
lowered blood-pressure is raised. 

[Heard (Am. Jour, of Med. Sci., 1913, vol. 135, p. 238) has recently 
observed a number of patients suffering from various diseases, to whom 
camphor was administered hypodermatically. He reports that doses 
ranging from- small doses of a few grains up to as much as fifty grains, 
produced no definite effects on the circulation. They also failed to 
favorably influence auricular fibrillation. — Tr.] 

BIBLIOGRAPHY 

Frey: Mitteil. d. Schweitz. Klin., 1896, series 4, No. 1. 
Joteyko: Trav. Solvav, 1904, vol. 6. 
Passler: Deut. Arch. f. klin. Med., 1890, vol. G4, p. 715. 
Wendelstadt: Plliiger's Arch., 1S99, vol. 70, p. 223. 

Alcohol. — It is proper to consider from this point of view the 
often repeated experience of the favorable effects of small doses of 
alcohol in circulatory failure. Kunkel states that "the unpre- 
judiced observation of physicians permits no other conclusion 
than that alcohol, at least in certain pathological conditions, exerts 
a favorable influence on the depressed cardiac and respiratory func- 
tions. A few spoonfuls of a good wine administered to a patient 
in profound collapse, with scarcely perceptible pulse and hardly 
perceptible respiration, and pallid cold face, often, after a few min- 
utes, cause color to reappear in the cheeks, as the pulse becomes fuller 
and the respirations deeper and more regular." On the other hand, 
there are many who deny these favorable effects. The stimulation 
of the respiratory centre, especially in conditions of fatigue, has been 
experimentally proved (see p. 47). If, as seems to be the case, alcohol 
under certain conditions favorably influences the circulation, this, 
according to our present knowledge, is to be attributed in part to its 
action on the heart, and in part to its vasomotor actions. On page 259 
it has been stated that recent experimental investigations have demon- 
strated that alcohol may bring about an improvement of the circula- 
tion, especially if the heart action be enfeebled. 



TREATMENT OF CIRCULATORY FAILURE 317 

The cutaneous vessels dilate even after small doses of alcohol, as 
a result of the diminution of their tone, but at the same time the 
pressure in the aorta rises somewhat. This alone renders it probable 
that other vascular systems must be contracted during the action 
of the alcohol, and, in fact, alcohol appears to constrict the visceral 
vessels, Dixon, by the use of the plethysmography having recently 
shown that the constriction of the intestinal vessels occurs coinci- 
dently with the rise in blood-pressure. According to this author, the 
splanchnic vasoconstriction is in part the result of an action on the 
centres, and it is this portion of the pharmacological action of alcohol 
which may perhaps be of value in conditions of circulatory failure. 
However, it is- certain that the vasoconstriction is in part due to 
peripheral actions, for it occurs even after the elimination of the 
vasomotor centres (Kochmann, Wood and Hoyt). 

In this way alcohol alters, the distribution of the blood by forcing 
it from the abdominal viscera and at the same time by dilating the 
peripheral vessels. As a result of the preponderance of the vaso- 
constriction, there is an improvement of the- circulation, especially 
if the blood-pressure were previously abnormally low, and in this 
way the blood flow through the heart is indirectly improved. In man, 
too, it is possible to demonstrate a rise in blood-pressure after small 
doses of 60-80 c.c. of 10 per cent, alcohol or wine (Binz). 

BIBLIOGRAPHY 

Bachem: Arch, intern, de Pharmacodyn., 1905, vol. 14, p. 437. 

Binz: Ther. d. Gegenw., January, 1899. 

Dixon: Journ. of Physiol., 1907, vol. 35. 

Haskovec: Arch, de med. exp., 1901, vol. 13, p. 539. 

Kochmann: Arch, intern, de Pharmacodyn., 1904, vol. 13, p. 329. 

Kunkel: Handh. d. Toxikol., 1901, p. 408. 

Wood and Hoyt: Mem. of the Nat. Sciences, Washington, 1905, vol. 10. 

Ether. — Next to camphor, ether is the drug most often used as 
an analeptic in conditions of failing circulation. The reflexes due to 
the sensory irritation at the place of application were formerly 
considered to be alone responsible for the favorable effect on the 
circulation which followed its subcutaneous injection or its internal 
administration (Hoffmann's anodyne in fainting). Recently Dcrou- 
mix, using plethysmography methods, found that small doses of 
other, just as is the case with alcohol, carried by the blood to the 
internal organs caused a vasoconstriction, so that under some cir- 
cumstances the blood-pressure may rise considerably. This is espe- 
cially the case if the blood-pressure was previously abnormally low. 
On the other hand, it has not been possible to demonstrate that ether 
exerts a favorable action on the isolated heart, although, according 
to Dcmuaur, the heart beating in the intact circulation beats more 
powerfully and rapidly while the blood-pressure is raised. This effed 
on the heart is, therefore, to be considered .is the result of the 



318 PHARMACOLOGY OF CIRCULATION 

better blood flow through the coronary vessels. The analeptic effects 
of ether, which have always been claimed by physicians, should, 
accordingly, be attributed to the improvement of the distribution of 
the blood resulting from stimulation of the vasomotor centres [and 
in addition to the local constricting effect on the splanchnic vessels. — 
Tr.] as well as to its stimulant action on the respiratory centre. 

BIBLIOGRAPHY 
Derouaux: Arch, intern, de Pharmacodyn., 1909, vol. 19. 

Saline Infusions. — It is passible in still another fashion to help a 
circulation which is failing as a result of vasoparesis. By increasing 
the volume of blood it is possible, for a time, to obtain the desired 
better supply of blood to the nervous system and to the heart. An 
internal hemorrhage, as it were, results from the relaxation of the 
splanchnic vessels, the total cross-section of the vascular tree thus 
becoming too large for the amount of blood present in the body. In 
such case the necessary rapidity of blood flow through the vital 
organs may be secured by a better filling of the vascular systems as 
well as by a constriction of the dilated vessels. In place of the dan- 
gerous transfusion of blood (often resulting in hemoglobinuria, 
damage to the kidneys, etc.), subcutaneous or intravenous infusion of 
indifferent isotonic salt solutions may be employed for this purpose. 
Of these the alkaline Ringer's solution which contains calcium is the 
best. [Direct arm to arm transfusion, especially advocated by Crile, 
has many advantages, but for obvious reasons it is not always avail- 
able.— Tr.] 

If the vascular tone be normal, such an artificial increase in the 
contents of the vessels will be removed from the circulation extremely 
rapidly, as was shown long ago by the experiments of Cohnheim and 
IAchtheim. If, however, the blood-pressure be low, the salt solution 
passes from the vessels into the tissues and the urine much more 
slowly and remains in the blood for a considerable period. When 
the splanchnic innervation is functioning normally, the splanchnic 
vessels are able to take up considerable excess of fluid, and, therefore, 
under normal conditions the blood-pressure is not markedly raised by 
saline infusions, even during the period in which the solutions intro- 
duced have not yet been removed from the blood. If, on the other 
hand, the splanchnic system is already overfilled as a result of vaso- 
motor depression, its capacity for absorbing more fluid is lessened, and 
thus the introduction of even moderate amounts of fluid markedly 
raises the blood-pressure and thus brings about an improvement of the 
depressed circulation (Passler). 

In such fashion saline infusions may act favorably in the de- 
pressed circulation of infectious diseases, and also by "washing out" 
various toxins and other poisonous substances (Dastrc, Sahli, Bosc, 
Lenhartz) so far as these are not firmly combined with the tissues, — 



TREATMENT OF CIRCULATORY FAILURE 319 

for example, diphtheria toxin (Enriques) . In case the body has lost 
large amounts of water, as in cholera and cholera morbus, infusions 
also counteract the dehydration of the tissues. It is to be remembered, 
however, that saline infusions can be of permanent value only in- 
directly (by favoring- the excretion of poisonous substances, etc.), 
for the vasomotor centres remain depressed, notwithstanding the better 
filling of the vascular system, so that, in spite of the fact that the 
blood-pressure is raised by the infusion, if the experimental infection 
be a grave one, sensory stimuli remain ineffective so long as the toxines 
causing the vascular paresis continue to be produced (Pcissler). 

The conditions are much more favorable for the life-saving action 
of infusions in cases where death is threatened from hemorrhage. 
Goltz was the first to assert that death after extensive hemorrhage 
at times occurred not because the amount of blood remaining was 
insufficient to maintain the internal respiration of the tissues, but 
because it was not sufficient to maintain the circulation. In true 
hemorrhage, just as in the so-called "bleeding" into the splanchnic 
system, the first endeavor of the organism is to supply sufficient blood 
to the vital organs by compensatorily constricting the vessels of the 
skin aud muscles. If this regulatory mechanism and the inflow of fluid 
from the tissues into the blood are not sufficient to bring about a 
sufficient flow of blood into the heart, cardiac weakness results just as 
in the case of paralysis of the vessels. 

Hardly any other symptomatic therapeutic effects may be better 
demonstrated than the reviving effect of saline infusion after an 
animal has been bled until respiration ceases and the pulse disappears. 

The experimental proof that saline infusions may save life after otherwise 
fatal hemorrhage was first attempted in experiments on dogs. Here, however, 
it was found to be difficult to estimate the amount of blood in the individual 
animals, for this varies within considerable limits. Loss of blood in amounts 
less than 4.G per cent, of the body weight are, as a rule, well borne, even without 
infusion, while if the blood loss exceeds 5.1-5.4 per cent., death usually ensues. 
However, the majority of the more recent observers are of the opinion that when 
hemorrhage readies this amount infusions are no longer able to preserve life 
permanently, hut that in spite of temporary success the dogs die later as a result 
of the loss of haemoglobin (Maydl, Schramm, Feis). However, there is no doubt 
that infusions regularly bring about rapid recovery in our experimental animals 
afdr hemorrhage, even if before the infusion the respiration lias ceased, the reflex 
excitability has disappeared, and the heart beats have become unrecognizable 
( Kronecker ) . 

According to all clinical experience, it appears that in man infu- 
sions have a greater life-saving power than in our laboratory animals 
(Schwarz, Schonborn, Kiittner, Laufer). This difference between 
clinical experience and the results obtained from animal experimenta- 
tion is probably due to the fact that the human vascular system, espe- 
eially after severe operations (chloroform narcosis), is not capable of 
adapting itself to large blood losses to so great a degree as is the 
vascular system of our laboratory animals. As ;i result, exsan- 
guinated men are much more likely to die from the mechanical 



320 PHARMACOLOGY OF CIRCULATION 

results of hemorrhage than are the latter (Leiclitenstern) . In the 
dog, for example, on account of the completeness with which the 
regulatory constriction of the splanchnic system compensates for 
hemorrhage, cessation of the respiration and disappearance of the 
pulse occur only when the bleeding is so great that it necessarily 
will result fatally on account of the loss of the red cells, while in 
man collapse appears to develop after much less severe hemorrhage. 
For the significance of transfusion in replacing blood-cells lost by hem- 
orrhage or otherwise rendered useless, see page 435. 

BIBLIOGRAPHY 

Bosc et Vedel: Compt. rend. Soc. de Biol., 1896. 

Dastre ct Loye: Arch, de Physiol., 1889, p. 253. 

Enriques et Hallion: Compt. rend. Soc. de Biol., 189G, p. 756. 

Feis: Virchow's Arch., 1894, vol. 138, p. 75. 

Goltz: Virchow's Arch., 1864, vol. 29. 

Kronecker u. Sander: Berl. klin. Woch., 1879, p. 768. 

Kronecker u. Sander: Korrespondenzblatt f. Schweiz. Arzte, 1886, Nos. 16-18, 

Kiittner: Beitrag f. klin. Chir., 1903, vol. 40, p. 609. 

Laufer: Zentralbl. f. d. Grenzgebiet d. Med. u. Chir., 1900, p. 422. 

Leichenstern : Volkmann's Vortr., 1890-94, No. 25. 

Lenhartz: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 189. 

Mavdl: Wien. med. Jahrbuch, 1884, No. 1. 

Passler: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 715. 

Sahli: Volkmann's Vortrage, 1890-94, No. 11. 

Schonborn: Handbuch d. spez. Path. u. Ther., Jena, 1895, vol. 2, p. 3. 

Schramm: Wien. med. Jahrbuch, 1885. 

Schwarz: Habilitations-Schrift, Halle, 1881. 

Epinephrin. — The most efficient means for the rapid restoration of 
the circulation in all conditions of vascular depression is the intra- 
venous injection of epinephrin. This aids the halting circulation 
in another way than do the above discussed vasomotor drugs, for it 
constricts the arterial path by acting locally on the vessel walls (p. 279) , 
and is able to restore the tone of the splanchnic vessels even after 
they have been completely relaxed as a result of vasoparesis of central 
origin. In this way, in spite of the persisting paralysis of the vaso- 
motor centres, the abnormal distribution of the blood is changed 
back to the normal so long as the epinephrin action lasts, for central 
stimulation of the vessels is replaced for the time being by an 
increased peripheral stimulation. As this drug is at the same time a 
powerful stimulant for the heart's action, it would be the ideal 
drug for combating circulatory failure if its action were not so 
fleeting. However, its good effects appear to last especially long 
when it is used in cases of circulatory failure. 

The revival by epinephrin of hearts poisoned by chloroform and 
potassium was demonstrated experimentally a good while ago (Gott- 
lieb). More recently it has been shown that animals dying as a 
result of poisoning by diphtheria toxin, with a blood-pressure as low 
as 30-40 mm. Hg, may be kept alive for as long as 7 hours if this 
drug be administered intravenously, the blood-pressure remaining at 



TREATMENT OF CIRCULATORY FAILURE 321 

a normal height for as long- as 30-40 minutes after a single injection 
(Fr. Meyer). The respiration improves and the reflexes return, while 
the weak and very slow pulse becomes strong and rapid. The drug's 
actions on both the heart and the vessels appear to be involved in this 
astonishingly successful experimental therapy. In consequence of the 
narrowing of the blood path, the rapidity of the blood flow is in- 
creased and the heart receives again the normal quantities of blood, 
while the ability of the heart to do this, in spite of the extensive 
damage done to it by the diphtheria toxin, is doubtless due to the 
direct action of the epinephrin in causing a strengthening of the 
contractions and an increase in their rate. 

In all cases of central vascular depression (e.g., poisoning by 
chloral hydrate, by depressing diphtheria toxins, etc.) or of peripheral 
paralysis of the splanchnic system (e.g., acute arsenic poisoning), in 
experiments on animals, epinephrin will bring the blood-pressure back 
again to the normal, although it may previously have fallen nearly to 
zero. 

Clinically, intravenous injections of epinephrin were first tried 
by L. Heiclenhain, who used it in combination with saline infusions 
in the circulatory failure of severe general peritonitis. [Crile, of 
Cleveland, recommended and used such injections! in the treat- 
ment of shock and other conditions of collapse considerably earlier 
than the above-mentioned author. — Tr.] In such conditions (perito- 
nitis) the pathological distribution of the blood results from the 
inflammatory, hyperemia of the mesenteric and peritoneal vessels, and, 
according to Ilehiecke, also from a depression of the vasomotor centres 
by bacterial toxins. According to Heidenhain's frequently corrob- 
orated experiences, this "internal hemorrhage" due to vascular de- 
pression may often be combated with striking success by the slow 
injection of about % mg. of epinephrin in %-l litre of physiological 
saline solution heated to the temperature of the body. In cases in 
which the patient is still able to overcome the infection, this procedure 
may be a life-saving one. 

Koilne's recommendation to add epinephrin to the fluid infused in 
cases of threatening death from hemorrhage is quite as rational, for 
thus not only are the Vessels better filled, but in addition their tone 
is improved. In accordance with the facts first observed experimen- 
tally, such experience of its use in man, as is at present available, 
has shown that these intravenous injections exert a powerful reviving 
influence in every form of collapse of the circulation. Thus, Kothe 
by intravenous injection of %-l m £- 0I " epinephrin was able to revive 
patients who, following spin.il anaesthesia, were moribund, without 
perceptible heart beat and with abolished corneal reflexes and inter- 
rupted respiration, as well ;is eases of severe post-operative shock. 
The heart action improved immediately, and after a few seconds the 
pulse could again be felt, and the respiration and other functions of 
21 



322 PHARMACOLOGY OF CIRCULATION 

the nervous system gradually returned to normal. Recently, John 
has reported favorable results from this procedure in most severe 
circulatory collapse in the course of pneumonia, septicaemia, etc. Even 
when all other analeptics ( strophanthin intravenously injected, caf- 
feine, camphor, etc.) had failed, the threatening cardiac weakness 
was at once relieved by i/o-l mg. of epinephrin, and often permanent 
life-saving results were obtained. 

In all such cases in which epinephrin is injected, the immediate 
strengthening of even a most alarmingly weakened heart action indi- 
cates that the direct action on the heart cooperates with the vasocon- 
stricting action, and this improvement of the circulation then brings 
about an improvement in the vitally important functions of the central 
nervous system. The extent to which such results may succeed in pre- 
serving life depends on whether the cause of the circulatory failure — 
for example, the vascular depression — still persists or whether, as in 
shock or chloroform poisoning, the circulation needs support for only 
a short critical period. No good can result from increasing the size 
of the dose injected at one time, but, on the contrary, too large doses, 
by causing too great a rise in the blood-pressure, are dangerous to a 
heart already overtaxed to its limit of endurance.* On the other hand, 
repeated injection of small doses is well borne. When one considers 
how fleeting is the effect of epinephrin in experiments on animals, 
the long duration of the effect produced by a single injection in man 
under these pathological conditions is very striking, the improvement 
in the circulation lasting sometimes 6-8 hours, and longer. It is 
probable that this is the result of the favorable effect on the vasomotor 
centres, they receiving for a time sufficient amounts of blood which 
thus favor their restoration to more normal function. 

Very recently the subcutaneous injection of epinephrin has been tried in 
the treatment of circulatory failure, large, doses (up to 6-10 rag.) being given. 
[The translator has seen the subcutaneous injection of 1 to 1.5 mg. followed by a 
very alarming rise in the blood-pressure and a whole clinical picture resembling 
closely the results of intravenous administration of large doses to animals. He, 
therefore, believes it proper to warn against the subcutaneous injection of large 
amounts. — Tr.]. However, this method of administration seems less rational than 
intravenous administration, inasmuch as epinephrin, by its local vasoconstricting 
action, prevents its rapid absorption, and therefore must remain inactive in the 
subcutaneous tissues. [Although, a priori, this would be expected, it has been 
indisputably shown that in man subcutaneous injections of epinephrin produce 
very distinct effects, and many clinical observations would indicate that its 
subcutaneous injection is frequently followed by more or less lasting improvement 
of the circulation. — Tr.] 

BIBLIOGRAPHY 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1S96, vol. 38, p. 00. 

Heidenhain, L.: Mitt. a. d. Grenzgeb. d. Med. u. Chir.. 1908, vol. 18, p. 837. 

Heinecke: Deut. Arch. f. klin. Med.. 1899. vol. 69, p. 429. 

John: Miinehn. med. Woch., 1909, No. 24. 

* [In the laboratory such large doses appear at times to cause fibrillation of the 
ventricle. Consequently care should be taken not to give too large doses. — Tr.] 



TREATMENT OF CIRCULATORY FAILURE 323 

Kothe: Tlier. d. Gegemv.. February. 1909. 

Kothe: Zentralbl. f. Chir., 1907, Xo. 33. 

Meyer, Fr. : Arch. f. exp. Path. u. Pharm., 1909, vol. 60, p. 20S. 

Winter: Wien. klin. Woch., 1905, Xo. 20. 

Digitalis Group. — A lasting improvement in the distribution of the 
blood might be expected to result from the constriction of the intes- 
tinal vessels which follows the administration of the members of the 
digitalis group. Experimentally it is possible by their use to raise the 
blood-pressure of infected animals — for example, in diphtheria 
(Pdssler, Meyer) — and it is not impossible that the successful results of 
the intravenous injection of strophanthin in conditions of collapse of 
the circulation are at least partly' due to the vasoconstriction which 
this drug induces (see p. 306).* 

BIBLIOGRAPHY 

Meyer, Fr.: Arch. f. exp. Path. u. Pharm., 1909, vol. 60, p. 208. 
Passler: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 715. 

TEEATMEXT OF VASCULAR CRISES AXD VASOCOXSTRICTION 
Without doubt tonic vasoconstriction plays an important, but as 
yet insufficiently understood, role in pathology. General contraction 
of the vessels and vasoconstriction in special regions must be separately 
considered. Of the general vasoconstrictions only those due to toxic 
agents are at all well understood. They may result from a stimulation 
of all the vasomotor centres, as, for example, in asphyxia or in strych- 
nine poisoning, or they may be due to a more or less general, peripher- 
ally caused vasoconstriction such as that following the intravenous 
injection of epinephrin. 

Both types also occur as endogenous pathological phenomena. 
Thus, the accumulation of carbonic acid in the blood, which results 
from insufficient arterialization, causes an over-excitability of the 
vasomotor centres, and this is probably the chief cause of the rise in 
blood-pressure observed in conditions of stasis [in combination with 
the increase of viscosity due to the excess of carbon dioxide. — Tr.]. 
A general increase in the peripheral vascular tone may, on the other 
hand, be due to a too free secretion of epinephrin in cases in which 
the inner secretion of the adrenal glands is pathologically disturbed. 

[This has been asserted to be the cause of the commonly observed 
hypertension of Bright 's disease, but this view has also been stren- 
uously combated. At present we are not in a position to state the 
cause of this hypertension, but can simply attribute it to an increased 
general vascular tone — Tr.] Finally, the vasomotor centres are sus- 
ceptible to manifold reflex influences and thus may be pathologically 

influenced by various distanl organs. 

*CriWs observations on dogs in Bhoek indicate tnat members of tbe digitalis 
group are not helpful, l>ut, on tbe contrary, are actually harmful in shuck. 



324 PHARMACOLOGY OF CIRCULATION 

A general increase of the vascular tonus has, as its first result, 
an alteration of the distribution of the blood, for all vascular systems 
are not equally constricted, the vessels in the splanchnic system being 
more affected than the others. The vessels of the skin and muscles 
by active dilatation serve a regulating purpose, while other vascular 
systems, such as that of the brain and that of the lungs, in a more pas- 
sive fashion adapt themselves to take up the blood squeezed out 
from the abdominal viscera. Overfilling of the brain with blood may 
therefore result from an insufficiently compensated vasoconstriction 
in the splanchnic system, and the insomnia of many individuals in 
high altitudes may be due to such moderate disturbances, for a high 
altitude causes an increase in the general vascular tone. Such disturb- 
ances in this compensatory regulation occur particularly in arterio- 
sclerosis, Romberg and 0. Mutter having shown that the vessels in the 
extremities react with increasing lack of promptness to the reflex 
action of heat and cold as the arteriosclerosis progresses. Vascular 
crises, therefore, are not so readily compensated for in arteriosclerotic 
patients as in normal individuals. 

Marked constriction of the splanchnic vessels — for example, that 
occurring in strychnine poisoning or in asphyxia — produces secondary 
effects on the heart, if the blood does not find sufficient accommodation 
in other regions, the pressure in the aorta rising and the blood 
accumulating in the heart and in the pulmonary circulation (^Yallcr). 
For these reasons it is clear that extensive vasoconstriction may cause 
a diminution of the pulse volume of the left heart, — i.e., a relative or 
absolute insufficiency of the heart, — and under these conditions vaso- 
dilating agents may indirectly improve the cardiac function. 

Local vasoconstriction in different parts of the body is much more 
common than general vasoconstriction. The cutaneous, cerebral, coro- 
nary, and intestinal vessels are especially likely to be thus affected 
(Pal). Spasmodic persistent contractions of the renal vessels may 
also occur as a result of reflex influences (reflex anuria) . 

Cold causes a constriction of the cutaneous vessels not only at the 
place of application but reflexly all over the whole surface of the body. 
If the vasomotor centres be very excitable, cold may thus be respon- 
sible for disturbances of the circulation. In a similar manner the 
toxins of various infections cause spasmodic contraction of the 
cutaneous vessels, and chills result. In certain forms of shock the 
same conditions may be observed, while in other conditions the con- 
traction of the cutaneous vessels may be brought about secondarily, — 
for example, through diminution of the amount of blood in certain 
anaemias or as a result of its concentration in the algid stage of 
cholera. 

Cutaneous vascular cramp causes pallor and a feeling of coldness. 
This type of vasomotor disturbance is especially likely to occur in 
the extremities, and ranges from that of slightest degree causing cold 
hands and feet up to the most severe type such as occurs in Raynaud 's 



TREATMENT OF VASOCONSTRICTION 325 

disease. These vascular crises in the internal organs cause the so-called 
vessel pain {Gefassclimerz) and attacks of functional disturbance in 
the organs whose blood supply is thus rendered intermittent (intermit- 
tent claudication). Such would appear to be the cause of stenocar- 
dial attacks or angina pectoris. The hypothetical explanation of such 
disturbances, as resulting from vascular cramp, often finds its best 
corroboration in the curative effect of vasodilating drugs or agents. 

In certain forms of migraine it would appear that chronic contrac- 
tion of the meningeal vessels is more or less responsible for at least 
a part of the trouble. Other varieties of headache — for example, that 
in fever and in uraemia — are also attributed to a spastic contraction of 
the cerebral vessels. It may be that sea-sickness also stands in some 
causal relationship to such tonic contraction of these vessels [see note, 
p. 325.— Tr.]. 

Finally, it would appear that in different conditions of stenocardia 
and related disorders the causal moment is a suddenly occurring 
contraction of the coronary vessels (R. Breuer). In such cases the 
vascular crises may occur simultaneously in several regions and may 
pass from one to another. For example, in angina pectoris the tonic 
contraction may extend from the cutaneous vessel of the upper ex- 
tremities to the coronary vessels. 

The general blood-pressure is affected by the local vascular crises 
only when these involve extensive vascular systems, as, for example, 
in the case of lead colic, where the intestinal vessels are tonically 
contracted. On account of the extent of the cutaneous vascular 
system in man, vascular crises limited to the vessels of this system 
may also affect the aortic blood-pressure. However, in most cases 
the blood forced out from the constricted system finds a place in other 
parts — for example, in the vessels of the brain — which dilate when 
the vessels of other regions are tonically contracted. This would 
appear to explain the frequently observed coincidental occurrence of 
"cold feet and hot head." 

The regional vascular crises are a result of autochthonously or 
reflexly caused excitation of the appropriate vasoconstrictor centres, 
but it appears that changes in the vessel walls, such as are found in 
arteriosclerosis and chronic nicotine poisoning, dispose to their occur- 
rence. In accordance with these facts, visceral crises may be relieved 
by drugs (narcotics) diminishing the excitability of the vasomotor 
centres, and also by those acting peripherally, which diminish the 
pathologically increased tonus of the vessel walls or render them less 
susceptible 1o the influence of the vasomotor centre. Caffeine and 
theobromine are examples of drugs acting in the latter fashion, while 
aniyl nil rite and the other nitrites, with their central and peripheral 
vasodilating action, take an intermediate position. 

The narcotics of the alcohol-chloroform group are of value as 
vasodilating drugs in so far as they, like alcohol, are otherwise not 
vi ry poisonous, or, like chloral hydrate, even in small doses [? — Tr.]. 



326 PHARMACOLOGY OF CIRCULATION 

depress the vasomotor centres. They act, it is true, on the vasomotor 
tone of all the vascular systems, but certain systems — above all, the 
cutaneous and the cerebral vessels — are especially readily dilated by 
them. Still more elective is the relaxing effect on the cutaneous 
vessels exerted by the members of the antipyrine group, which will be 
further discussed in the section on the pharmacology of temperature 
regulation. These drags are especially efficient in relieving the 
tonic contraction of the cutaneous vessels which occurs in chills. 
These antipyretic and sedative drugs, moreover, influence the circu- 
lation of the brain in even smaller doses. As shown by Wiechowski, 
antipyrine and related drags, in febrile animals, cause, as their first 
appreciable vasomotor effect, a distinct dilatation of the intracranial 
vessels, while the narcotics — for example, chloral hydrate — increase 
the flow of blood through the brain only as one of the effects of a 
very wide-spread vasodilatation. It may be that the favorable action 
of chloral hydrate and other hypnotics in sea-sickness * rests on such 
a dilatation of the cranial vessels (Binz). 

The vasodilating action of moderately concentrated alcohol 
(brandy or strong wine) produces quick and useful effects when the 
cutaneous vessels are tonically contracted, — as, for example, in chills 
or in the faulty reaction which results from a persistent contraction 
of these vessels following a cold bath. Alcohol may also prove useful 
in certain cases of angina pectoris (Sahli). 

It is probable, too, that the favorable effect of alcohol in certain 
conditions of collapse, in which the circulatory failure is the result 
of faulty heart function, is to be explained by the rapid lessening of 
the tension of the vessels which is produced by proper doses. How- 
ever, it should be remembered, in this connection, that small doses 
of alcohol dilate the cutaneous vessels, and that, according to more 
recent experiments (p. 274) , they constrict the visceral vessels. It may 
be, however, that doses, which produce no effect on the blood-pressure 
in the normal circulation, will depress the tone of vessels tonically 
contracted. 

BIBLIOGRAPHY 
Binz: Zentralbl. f. inn. Med. 3 1903, No. 9. 
Breuer, K.: Miinchn. med. Woch., 1902, No. 39. 
Miiller, 0. : Deut. med. Woch., 190G, No. 39. 
Pal: Die Gefasskrisen, Leipzig, 1905. 
Romberg : 21. Kongr. f. inn. Med., 1904. 
Sahli: 19. Kongr. f. inn. Med., 1901. 

Waller: Ludwig's Arb. a. d. Physiol. Anstalt zu Leipzig, 187S. 
Wiechowski: Arch. f. exp. Path. u. Pharm., 1902. vol. 48, p. 376. 

* [It would appear fairly certainly established that sea-sickness is the result 
of the effect produced by the movements in space of the labyrinth of the ear, and 
that vasomotor phenomena are, as it were, simply the reflexly produced effects 
of this. If, as appears to be the case, the hypnotic drugs do favorably influence 
the symptoms of sea-sickness, a more plausible explanation would be that they 
do so' partly by interfering with the reflexes and partly by lessening the unpleas- 
ant subjective symptoms of this condition, for both of these effects would result 
from their general depressing influence on the central nervous system. — Tk.] 






TREATMENT OF VASCULAR SPASM 327 

The Nitrites. — Amyl nitrite and similar drugs are the most rapid 
and powerful vasodilating agents which, we possess. They are the 
vasodilators par excellence. As may be shown by direct observation, 
the action of small doses is electively limited to dilatation of the 
cutaneous vessels of the upper part of the body and those of the 
brain, while in larger doses, by action on the centres, they relax 
the vessels throughout the body [with the exception of the pulmonary 
vessels. — Tr.] In addition, they also act locally on the vessel walls, 
as shown by their effect on the coronary vessels. Lauder-Brunton 
introduced amyl nitrite into the therapy of angina pectoris in 1867, 
and in practice this drug has shown itself extremely effective symp- 
tomatically in the treatment of this condition. 

As is well known, the symptom-complex of angina pectoris occurs 
in heart disease of different types, and consists in sudden attacks of 
precordial pain associated with a feeling of anxiety and depression, 
which may be accompanied by more or less marked dyspnoea. Pathol- 
ogists believe that it is probably caused by a sudden interference 
with the blood supply of some portion of the heart, for, at the autopsy 
of such cases, sclerosis of the coronary arteries, causing narrowing 
at their mouths or in their course', is often found. It may, there- 
fore, be assumed that the chief cause of these attacks is a diminished 
blood flow in the coronary arteries or their faulty power of accommo- 
dation to the need of an increased blood supply to the heart (Krehl). 
If this be so, it is easy to understand the successful results of the 
administration of a drug possessing such exquisite vasodilating actions. 

The most probable supposition concerning the method by which 
this effect is produced would be that amyl nitrite possesses special 
powers of dilating the coronary arteries by action on the vasomotor 
centres controlling these vessels. Unfortunately, our knowledge of 
their central innervation does not permit us to state that the drug 
exerts this elective action. On the other hand, Loeb's investigations 
have proved that amyl nitrite may dilate the coronary vessels by a 
local action on their walls. 

Furthermore, the vasodilatation produced by amyl nitrite may 
diminish the demands made on the heart in case constriction of 
vessels in other regions has caused a relative cardiac insufficiency. 
Thus, the favorable action of amyl nitrite in angina pectoris may 
be explained quite apart from any direct action on the coronary 
circulation, for it may be due to the lessening of the resistance against. 
which the heart must work, resulting from the immediate vasodilata- 
tion which follows the administration of this drug. In cases of 
stenocardia the efficiency of other vasodilatating drugs — for example, 
alcohol — may be explained in a similar fashion. [As it has been 
shown by McKenzu and others thai angina pectoris frequently 
occurs without any evidence of general vasoconstriction and in the 



328 



PHARMACOLOGY OF CIRCULATION 



presence of normal blood-pressure, it does not appear probable that 
the relief which it so often gives in this condition is a result of its 
general vasodilating action. — Tr.] 

Amyl nitrite does not always entirely or even partially relieve 
the attacks of angina pectoris, nor should this be expected, for it 
would appear that this symptom-complex often results from different 
causes. Consequently, success should be expected to result from its 
administration only when extensive vasoconstriction is the exciting 
cause. [ ? See above. — Tr.] Its efficiency is most readily understood 



a. Tense pulse (.angina pest). 6. After amyl nitrite. 



NMvAAAAAAMM 



Tense pulse before amyl nitrite. 



^ 



After five drops of amyl nitrite {Pal). 
Fig. 36. 



in those forms of angina described by Nothnagel as angina pectoris 
vasomotoria, in which "pallor and numbness, subjective feeling of 
cold, and objective decrease in temperature of the skin" would indi- 
cate that the tonic contractions of the cutaneous vessels inaugurate 
the attack. 

The effects of the inhalation of a few drops of amyl nitrite appear 
extremely rapidly, in less than a minute, and often last an extremely 
short time, but frequently the temporary vasodilatation produced is 
able to correct the pathological conditions for a considerable period. 
Lauder-Brunton thus describes a case in which he first used amyl 



TREATMENT OF VASOCONSTRICTION 329 

nitrite. ' ' Simultaneously with, the flushing of the face the pain disap- 
peared completely, and did not return until the following night. 
"While sometimes the pain returned after about five minutes, renewed 
inhalation of a few drops caused it to disappear again, and this 
time for a considerable period." At the same time with the relief 
of the attack, the cessation of the tonic contraction of the vessels 
is clearly seen in the radial pulse. This is graphically shown in 
sphygmograms taken by Lauder-Brunton. 

Amyl nitrite has also been used in other conditions of disease in 
which more or less tonic contraction of the vessels — for example, of 
the cerebral vessels — has been assumed. In this connection, the use 
of amyl nitrite would appear rational in certain types of migraine 
in which a striking pallor of the face indicates vascular constriction 
(hemicrania sympathico-tonica) . Quite beyond question is the effect 
of this drug on the tonic contraction of the splanchnic vessels when 
it is used in lead colic, the abnormally tense and retarded pulse 
becoming, at least temporarily, quite normal (Fig. 37) {Frank, 
Biegel) : 




(6) 
Fig. 37.— a, pulse during lead colic; b, after amyl nitrite. 

The various nitrites act analogously to amyl nitrite, but in general 
produce more lasting effects. After sodium nitrite (in doses of 0.03- 
0.06 eg.) the effect is produced in 3^1 minutes, reaches its maximum in 
15-30 minutes, and lasts about 1% hours (Marshall, M. Hay). 

As a general thing, however, the action of sodium nitrite is con- 
sidered to be less certain, while larger doses — e.g., 0.5 gm. — produce 
toxic effects. 

The nitric acid esters of the higher alcohols also possess a pro- 
nounced nitrite action. Thus, nitroglycerin, in the very small amounts 
of }/,-l mg., produces in two minutes the same actions on the vessels 
<-is the nitrite salts. This similarity in the effects of the nitric acid 
esters with those of the nitrites is due to the fact that the former are 
changed in tin- body into nitrites. Nitroglycerin possesses the advan- 
tage over amyl nitrite in that its effects last longer (V/U-3 hours) 
[see above. — Tr.]. The same is true of erythrol tetranitrate and 
other similar compounds. It is stated that sodium nitrate in larger 
doses acts similarly to the nitrites (If. Hay), perhaps because in the 
body it is partially reduced to a nitrite. 



530 PHARMACOLOGY OF CIRCULATION 



BIBLIOGRAPHY 

Frank, A.: Arch. f. klin. Med., 1875, vol. 10. 

Ihiy, M.: The Practitioner, 1883. 

Krehl : Die Erkrankungen d. Herzmuskels, in Xothnagel's Spez. Path. u. Ther., 

YYien, 1901, p. 153. 
Lauder-Brunton: Clin. Soc. Rep., London, 1870. 
Lauder-Brunton : Deut. med. Woch., 1902, No. 16. 
Lauder-Brunton: Lancet, 1S67. 
Lauder-Brunton: Pharmaceut. Journ., 1888. 
Loeb: Arch. f. exp. Path. u. Pharm., 1903, vol. 51, p. 04. 
Marshall : A Contribution of the Pharmacol. Action of the Organic Nitrates, 

Manchester, 1899. 
Nothnagel: Ztschr. f. klin. Med., 1891, vol. 19. 

Caffeine and theobromine and related substances dilate the vessels 
in certain regions by a peripheral action on the vessel walls. On 
page 274 it has been stated that caffeine, by its action on the vasomotor 
centres, produces an opposite (vasoconstricting) effect, which affects 
especially the visceral vessels that are particularly easily influenced 
by the vasomotor centres. There is thus an antagonism between 
its central vasoconstricting action and its direct peripheral vasodilat- 
ing action, in one group of vessels the peripheral action predominating, 
and in another the central. As long as the kidney remains under the 
influence of the vasomotor centres, as a general rule its vessels will 
be constricted by caffeine [?Tr.], and to a greater or less extent 
according to the varying individual susceptibility of the vasomotor 
centres to the action of the drug. On the other hand, caffeine always 
acts as a vasodilator in a kidney isolated from its nervous connec- 
tions. With theobromine, which has less action on the centres, the 
vasodilating action on the renal vessels always preponderates. (See 
section on diuresis.) 

Next to the renal vessels the cerebral arteries are especially 
affected by the peripheral action of caffeine. Wiechowski observed, 
during the action of caffeine, not only an increased flow through 
the brain, which he explained as the passive result of the forcing out 
of the blood from the splanchnic system, but also a direct depression 
of the tone of the intercranial vessels. The curative action of 
caffeine in certain types of headache may be due to this action on 
the cranial circulation. 

Finally, experiments of Hedbom and Loeb indicate that caffeine 
distinctly dilates the coronary vessels by a peripheral action on the 
vessel walls, as it does this in the isolated perfused heart. Theo- 
bromine acts similarly, and this is probably the explanation of the 
fact that theobromine preparations have proven so satisfactory in 
the prophylaxis of anginal attacks [and in other vascular crises. — 
Tr.] . During the attacks, however, it cannot be used, as its absorption 
is too slow to relieve promptly the tonic contraction of the vessels. 
The prophylactic employment of 2.0-2.5 gm. of theobromine-sodium 
salicylate prevents or moderates these attacks in unmistakable fash- 



TREATMENT OF VASOCONSTRICTION 331 

ion, as has been, evidenced by numerous observations made since it was 
first recommended for this purpose by Askanazy. Theobromine and 
the closely related theocin have also been found useful in the prophy- 
laxis of other conditions dependent on vascular crises. This is prob- 
ably due to the fact that the depression of the peripheral tonus of the 
vessels resulting from the action of these drugs renders them less 
susceptible to the occasionally recurring excitation of the vasomotor 
centres {Breuer). 

The alkaloid yohimbin (p. 289) also dilates certain vascular systems 
by a peripheral action. Its nitrate, vasotonin, in probably superfluous 
combination with very small amounts of urethane, has been recently 
recommended for subcutaneous injection in the treatment of angina 
pectoris or other arteriosclerotic disturbances (Muller u. Fellner, 
Staehelin). 

BIBLIOGRAPHY 

Askanazy: Deut. Arch. f. klin. Med., 1895; Deut. Zentralbl. f. klin. Med., 1895. 

Breuer, R.: Miinchn. med. Woch., 1902, Nos. 39-41. 

Hedbom: Skand. Arch. f. Physiol., 1899, vol. 9, p. 1. 

Loeb: Arch. f. exp. Path. u. Pharm., 1903, vol. 51, p. 64. 

Muller, Fr., u. Fellner: Therap. Monatshefte, 1910, June. 

Staehelin: Therap. Monatshefte, 1910, September. 

Wiechowski: Arch. f. exp. Path. u. Pharm., 1902, vol. 48, p. 376. 



CHAPTER IX 
PHARMACOLOGY OF THE RESPIRATION 

The respiratory system of mammals consists in the integral por- 
tions of the respiratory tract, the larynx, bronchi, and lungs, and in 
the muscles which control them, these being, in part, the striated 
laryngeal, intercostal, and diaphragmatic muscles and the unstriped 
muscles of the bronchi. The respiratory exchange of gases in the 
pulmonary alveoli depends on the atmospheric pressure, the activity 
of the motor mechanism of the respiratory muscles, and the elasticity 
of the pulmonary tissues, — i.e., on the mechanical effects of the 
respiratory movements, as well as on the resistance which opposes 
the movement of the air in the air-passages, and the elastic contraction 
and relaxation of the alveoli. 

The frequency, extent, and power of the movements of respiration 
are directly dependent on the state of excitation of the respiratory 
centres, situated in the medulla and spinal cord, which are stimulated 
directly by substances present in the blood and reflexly through cen- 
tripetal nerves, especially the pulmonary vagus, the trigeminus, 
and the cutaneous nerves. 

Of the factors which influence the excitation of the respiratory 
centre through the blood, oxygen and carbon dioxide tension are 
the decisive ones. Abnormally diminished 2 tension in the blood 
increases the frequency and depth of the respiration, causing, as a 
rule, a dyspnoea of a predominatingly inspiratory type, but this 
occurs only when the 2 content of the inspired air has sunk to 10 
per cent, or less (Speck, Loetvy, v. Terray). If at the same time 
the tension of C0 2 is very low, lack of 2 causes Cheyne-Stokes res- 
piration (Haldane and Douglas). This is the explanation of the 
appearance of this phenomenon in high altitudes (Durig). 

Oxygen Inhalations. — No appreciable effect on the respiratory 
apparatus or on the consumption of 2 and the total metabolism 
results from an increase of the 0, contents of the air respired, even 
when this amounts to 100 per cent. (Durig, Kraus) . Except in CO 
poisoning there is no sufficient scientific proof of the value of inhala- 
tions of 2 , although these have recently been strongly recommended 
by clinicians (McKenzie et al.) . 

Most observers, however, report that the inhalation of 2 exerts a 
favorable effect on the subjective feelings of patients suffering with 
dyspnoea and cyanosis, — at any rate, as long as the inhalation is 
continued. Inasmuch as haemoglobin cannot absorb more oxygen from 
a gas mixture rich in 2 than from the air, this effect cannot be 
attributed to a greater saturation of the blood-coloring matter with 
332 



DIRECT RESPIRATORY STIMULANTS 333 

oxygen. However, the plasma can absorb more oxygen if the oxygen 
tension of the inspired air is higher than in the ordinary air, and 
thus it may at times be of some importance to increase the oxygen 
tension in the inspired air (Durig), for plasma saturated with oxygen 
to an abnormally high degree may raise to the normal the oxygen 
tension in blood which is unequally, and therefore incompletely, arte- 
rialized on account of the existence, here and there in the lungs, of 
pathological conditions interfering with the gaseous interchange be- 
tween the blood and the air. It may be that, as a result, the metabolic 
products which cause dyspnoea are more rapidly oxidized, and that 
thus the restlessness and the feeling of anxiety due to the dyspnoea 
may be relieved. 

If, as a result of persistent over-saturation of the blood with C0 2 
in pulmonary stasis of cardiac origin, or as a result of uraemie poison- 
ing, the respiratory centre has been blunted to the stimulation pro- 
duced by C(X, an insufficient oxygen supply frequently, in spite of 
high CO. tension of the blood, causes a condition to develop which is 
characterized by periodic breathing, the patient falling asleep during 
the pauses and waking suddenly and anxiously when the respirations 
start again. In such conditions inhalation of 2 can often bring about 
regular breathing once more and thus give marked relief (personal 
communication, B. Breuer). From the above, the symptomatic effects 
of the inhalation of (X, especially those obtained as long as the inhala- 
tion continues, may be explained (see also Loewy and Zuntz). 

Effects of the Carbon Dioxide Tension of the Blood. — On 
the other hand, a diminution of the normal CO., tension in the alveoli, 
and consequently also in the tissues, has no stimulating effect on the 
respiration, while an increase of the CO. tension, even a very slight 
one, markedly stimulates respiration (Jacquct). Increased C0 2 ten- 
sion in the tissues also occurs if the alkalinity of the blood be dimin- 
ished, a condition which may result from the formation of acid 
metabolic products during hard muscular work or in fever, diabetes, 
many poisonings, etc. (Geppert and Zuntz). In such case the res- 
piration becomes very dyspnoeic. It is enlightening that under such 
conditions the free administration of alkalies may quiet and regulate 
the respiration. 

Effects of Body Temperature. — Without regard to its chemical 
composition, the temperature of the blood also exerts an influence on 
1 ii< • frequency and depth of respiration, increased temperature usually 
stimulating (Fick n. Goldstt in, v. Mertschi/nsky, Fridericq, R. II. 
Kahn) and lowered temperature depressing it. Therefore, all agents 
which warm abnormally cooled blood -for example, warm perfusions 
— or which, like the antipyretics, cool the overheated blood of fever 
will aid in bringing the frequency of the respirations back toward 
the normal. 



33-t PHARMACOLOGY OF THE RESPIRATION 



BIBLIOGRAPHY 

Durig: Wien. akad. Denkschr., 1910, vol. SG, p. 374. 

Durig: Engelmann's Arch., 1903, Suppl., p. 209. 

Kick u. Goldstein: Wurzburg. Verh., 1871, No. 7. 

Fick u. Goldstein: Pfliiger"s Arch., 1872, vol. 5, p. 38. 

Fridericq: Dubois' Arch., Suppl., 1883, p. 51. 

Geppert u. Zuntz: Pniiger"s Arch., 1888, vol. 42, p. 189. 

Haldane and Douglas: Journ. of Phvsiol., 1910, vol. 38, p. 401. 

Jaquet: Arch. f. exp. Path. u. Pharm., 1892, vol. 30. 

Kahn, R. H.: Engelmann's Arch., 1904, Suppl., p. 81. 

Kraus: Ztschr. f. klin. Med., 1893, vol. 22, p. 449. 

Loewy: Plliiger's Arch., 1894, vol. 58, p. 409. 

Loewy: Unters. iiber d. Resp. u. Cir. bei And. d. Druckes u. d. Sauerstoffgehalts 

d. Luft. Berlin, 1895. 
Loewy u. Zuntz: in Michaelis. Sauerstofftherapie, Berlin, 1905.' 
MeKenzie, James: Diseases of the Heart, 
v. Mertschinsky: Wiirzb. Verb., vol. 16, 1881. 
Speck: Physiol, d. menschl. Atmens, Leipzig, 1892. 
v. Terray: Pfluger's Arch., 1897, vol. G5, p. 383, here literature. 

DIRECT OR CENTRAL RESPIRATORY STIMULANTS 

In cases of severe illness or poisoning, deep coma not infrequently 
develops, the breathing becoming progressively slower and shallower 
and finally entirely insufficient. In such case the therapeutic indica- 
tion is to stimulate the respiration, — i.e., to excite the halting mechan- 
ism to sufficient activity. This can be accomplished by direct stimu- 
lation of the respiratory centre. 

The number of substances which directly stimulate this centre is 
very large. It may be stated that all very volatile poisons stimulate 
the respiration, and inasmuch as these substances are excreted in the 
expired air, this stimulation of the respiration is a reaction of the 
organism readily understood from the teleologic point of view. Hy- 
drogen sulphide, HCN, C0 2 , chloroform, ether, alcohol, amyl nitrite, 
and many others, all act in this fashion, but, for therapeutic purposes, 
only alcohol and ether are of practical importance in this connection. 

Alcohol. — The stimulating effect on the respiration exerted by 
small amounts of strong wines has long been known clinically; but 
the question, as to the extent to which this is a reflex effect from 
the stimulation of the taste and smell or of the sensory nerves of the 
stomach, or the result of direct stimulation of the respiratory cen- 
tres, has been responsible for numerous investigations, especially on 
the part of Binz and his pupils. 

These authors have been able, in animal experiments, to show that a 
persistent increase of the ventilation volume — i.e., of the volume of air 
breathed in and out in the unit of time — resulted from the administra- 
tion of alcohol irrespective of the manner in which it was administered. 
This occurred even after intravenous injection, while, when the alco- 
hol was injected toward the centre into the carotid artery, the effect 
was produced almost instantaneously (Wilmanns). From this last- 



DIRECT RESPIRATORY STIMULANTS 335 

mentioned observation it is permissible to deduce a direct stimulating 
action in the central nervous system. Moreover, as alcohol, unlike 
carbohydrates and fats, cannot be stored up, but is promptly com- 
busted, a part of the persistently increased respiration must be attrib- 
uted to the larger demand for 2 and the greater production of C0 2 
resulting from the combustion of the alcohol {Henri jean, Zantz) . As, 
however, this action occurs even after the intravenous administration 
of very small doses, whose combustion can hardly produce such effects, 
the chief cause of the increased respiration must be sought in a direct 
central stimulation. According to Binz, the ethers present in wines 
also possess the property of stimulating the respiratory centres. 

Ether may be administered internally either pure or mixed with 
alcohol in Hoffmann's anodyne. Subcutaneous injections of ether are 
also very efficient, but they must not be administered in the neigh- 
borhood of nerve-trunks. [Administered in these varying fashions 
this drug strongly stimulates the respiration partly reflexly and partly 
directly.— Tr.] 

In addition to the above-mentioned volatile substances, the respira- 
tory centre is stimulated by a number of drugs which increase the 
excitability of different portions of the central nervous system. In 
this connection, particular mention should be made of strychnine, 
camphor, caffeine, cocaine, atropine, and other alkaloids of this group, 
lobeline, apomorphine* and the two alkaloids contained in quebracho 
bark, aspidospermine and quebrachine (B. Wallace). For practical 
purposes, only camphor, caffeine, and atropine need be considered. 
[Strychnine! — Tr.] 

The stimulating action of camphor and the methods of its adminis- 
tration have already been discussed, as also that of caffeine. In this 
connection it may be mentioned that other substances, which may be 
obtained by distillation and which increase the frequency of respira- 
tion, are contained in tea and coffee (Heinz, Archangelsky) . 

BIBLIOGRAPHY 

Archangelsky: Arch, intern, de Pharmacodynamic, 1900, vol. 7, p. 405. 

Harnack: Arch. f. exp. Path. u. Pharm., 187-3, vol. 2, p. 254. 

Heinz: Inaug.-Diss., Bonn, 1800. 

Henrijean: Bull, de l'acad. r. de Bruxelles (3), 1883, vol. 5, Xo. 1. 

Krautwig, I'.: Zentralbl. f. klin. Med., 1893, No. 17. 

Wallace, B.: Proc. Soc. f. Exp. Biol, and Med., New York, 1903-4, vol. 1. 

Wendelstadl : Pfltiger's Arch., 1899, vol. 70, p. 223, lit. here. 

Wilmanns: Pfltiger's Arch., 1897, vol. 66, ]». 107. 

Zunt/.: Verh. d. Berl. phys. Ges., Dubois' Arch., 1SS7, p. 17s. 

Atropine. — The central stimulation of respiration by atropine 
was demonstrated long ago by Bezold and has been confirmed by 

* Apomorphine stimulates the respiratory centres even after the vomiting 
centres have been paralyzed in narcosis I Earnack) . | It later depresses them. — Tr.] 



336 



PHARMACOLOGY OF THE RESPIRATION 



various other observers. It is especially usefully and clearly devel- 
oped in narcotic poisonings, — for example, in chloral poisoning (H use- 
ma nn) and particularly in morphine poisoning. The following curve 
(Fig. 38), reproduced from Vollmer, shows graphically the results 
obtained in an investigation of the antagonistic action of morphine and 
atropine on the respiration. 

As large toxic doses of atropine may themselves depress the respira- 
tory centres, the desired success depends evidently on the skilful and 
careful use of atropine, and this depressing action explains the failures 
observed in the experiments of various investigators (Binz). 





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Indirect reflex stimulation of the respiratory centre usually 
produces more marked effect on the respiration than that caused by 
the use of drugs. Such reflex stimulation may be induced by cuta- 
neous irritation (seep. 341) and by irritation of the nerve-endings 
of the trigeminal and olfactory nerve in the nose, induced mechani- 
cally, as by tickling, or chemically, as by ammonia or vinegar. The 
widely used smelling salts contain ammonium carbonate with ethereal 
oils, such as the oil of lavender. 



BIBLIOGRAPHY 

Bezold u. Blobaum : Wiirzb. physiol. Untersuchungen, 1867, vol. 1, p. 1. 
Binz: Berl. klin. Woch., 1896, p. 885. 

Husemann: Arch. f. exp. Path. u. Pharm., 1877, vol. 6, p. 443. 
Vollmer: Arch. f. exp. Path. u. Pharm., 1892, vol. 30, p. 385. 



RESPIRATORY SEDATIVES 



337 



RESPIRATORY SEDATIVES 

The clinical indication is much oftener that of quieting and 
regulating the respiration than that for stimulation. This is the case 
where a directly or reflexly induced dyspnoea, spasmodic respiratory 
movements, or distressing cough demand relief, in which conditions 
symptomatic relief may be obtained by dulling the sensibility of the 
respiratory centres. 

This property of diminishing the excitability of the respiratory 
centres is possessed by all so-called narcotics, — i.e., by all substances 
which depress the excitability of the central nervous system, — but 
the various narcotics exhibit marked and important differences in this 
respect. Although all the anaesthetics and hypnotics, belonging to 
the large "alcohol group," have a sedative action on the respiration, 
this effect results only from more or less toxic doses, which appreciably 



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6 7 8 9 70 7f 72 73 M 75 76 77 78 73 W 27 22 23 Zi 25 36 27 

Normal curve. Chloralamide 

.V/orp/t. mur. Amylene hydrate 

Chloral hydrate Natural sleep 



Fig. 39. — Respiratory volume with increasing CO2 tension of the blood. 

or very decidedly blunt the consciousness, the sensibility, and the 
reflex excitability. They are consequently not suitable drugs for this 
indication. [The translator most emphatically disagrees with this 
sweeping statement, for he believes that clinically such drugs as 
chloral and other commonly used hypnotics may frequently be em- 
ployed with advantage for this indication and in doses which produce 
only moderate hypnotic effects.] 



MORPHINE 
On the other hand, the narcotics of the morphine group depress 
the excitability of the respiratory centre in a very specific fashion, 
long before, or without at all, producing other sedative effects. 

.1. Ldiiii/ 1 1 ; 1 s introduced, as a very useful means of measuring the excita- 
bility of the respiratory centre, the readily graded stimulation which results 
from mixing diU'creiil percentages of CO, with the inspired air. In man the 
expired air contains about •'! per cent, of C0 2 . If the inspired air be mixed with 
22 



338 PHARMACOLOGY OF THE RESPIRATION 

increased quantities of C0 2 , the C0 2 content of the expired air rises accordingly 
and may serve as a measure of the effective C0 2 tension in the blood. It has 
been shown also that as the percentage of C0 2 in the expired air rises from 3 per 
cent, to about 7 per cent, the respiratory volume increases almost exactly pro- 
portionately, and in the same proportion in different individuals and at different 
times. The curves in Fig. 39, reproduced from Loew-y, show this clearly. 
Apparently with higher C0 2 tension a summation effect from different unknown 
factors develops, for the ventilation volume increases to a greater extent than 
corresponds to the increase of C0 2 in the expired air. 

Neither natural sleep nor that induced by hypnotics, such as 
chloral hydrate, chloralamide, amylene hydrate, markedly influences 
the reaction curve, but this is decidedly altered by morphine, even 
in small doses which otherwise produce no sedative effects. Under 
its influence the respiratory centre becomes less excitable, so that the 
C0 2 in the inspired air must -be increased much more than under 
normal conditions in order to cause the usual increase in respiration. 
The sensibility of the respiratory centre to reflex stimulation — such, 
for example, as that resulting from stimulation of the sciatic — is dimin- 
ished in the same fashion as its sensibility to CO.. 

In man, after very small doses of morphine (3-10 mg.) the dimin- 
ished excitability of the respiratory centre expresses itself by slowed 
and deepened breathing-, for a stronger summation of the stimuli 
(distention of the lungs and the C0 2 tension in the blood) is needed 
to excite the rhythmic respiratory movements. This has been proven 
experimentally by A. Frankel, who observed that the respirations of 
rabbits under the influence of morphine occurred less frequently 
but were much deeper. 



Effects of Small Doses of Morphine on the Respiratory Volume 
of the Rabbit* 



Time, 


No. of respira- 


C.c. of air re- 


C.c. of air in 


minutes 


tions per min. 


spired per min. 


each respiration 


1 


68 


300 


4.4 


2 


64 


300 


4.6 


3 


68 


300 


4.7 


5 








13 


54 


300 


5.7 


26 


60 


400 


6.6 


51 


52 


360 


6.9 


61 


50 


440 


8.8 


71 


56 


500 


8.9 



* 0.54 ms. morphine per kilo injected subcutaneously. 

Under certain conditions, morphine may thus increase the ventila- 
tion in the lungs beyond the normal, for during each respiration only 
a portion of the alveolar air can be replaced by atmospheric air, and 
this portion, on account of the volume of air contained in the so-called 
"noxious air-space" of the trachea and bronchi, must be considerably 
increased by a deep respiration as compared to the amount replaced 



RESPIRATORY SEDATIVES 339 

during a shallow one. Thus, for example, in the experiments of 
Reach and Roder (see also Loeivy) the alveolar air was found to con- 
tain 17 per cent, of 2 and 2.7 per cent, of carbonic acid when 
20 litres of air were respired as a result of 100 respirations to the 
minute. "When the respirations were deeper and slower, the same 
"minute volume" was respired with only 25 respirations to the minute 
and the 2 in the alveolar air was found to be present in the propor- 
tions of 19.3 per cent, and carbonic acid in that of 2 per cent. In 
these figures the greater ventilating effect of deep and slow breathing 
is clearly apparent. 

This effect is increased by the fact that the composition of the 
air in all parts of the lungs is not the same, for the air is richest in 
C0 2 and poorest in 2 in the alveoli lying at the periphery, which 
expel their contents only during deep breathing and more especially 
during forced expiration. For this reason forced expirations, such as 
occur in coughing but especially during sneezing and vomiting, may 
exert a favorable influence on the renewal of air in the alveoli. 
Herein may lie a partial explanation of the benefit of the nausea and 
the retching movements, which the so-called nauseating expectorants 
induce (Dreser). 

From such slowed and deepened and, in spite thereof, more effi- 
cient respirations, the lungs and the whole respiratory system may 
experience a beneficial relief, and there may result a saving of strength 
which may be of greatest importance in enfeebled patients, who have 
been breathing frequently and ineffectively, — as, for example, cardiac 
cases or cases with high fever. By regulating and improving its 
efficiency, morphine does about the same for the respiration as digitalis 
<'ocs for a diseased and insufficient heart. 

Effects on Cough. — The reflex excitability of the cough centre, 
which is reflexly stimulated by irritation of the laryngeal and bron- 
chial mucous membranes and perhaps also by reflexes from other 
organs, is depressed by drugs of the morphine group even earlier 
and more readily than is that of the respiratory centre proper. This 
fact has been established clinically beyond all doubt, although experi- 
mental proof of it is still lacking, and consequently drugs of the mor- 
phine group may be used with good effect in conditions where the 
indication is to suppress the cough reflex, as in harassing or painful 
cough, or with the idea of avoiding lucmoptysis, or to relieve laryngeal 
inflammation or irritation, which is constantly aggravated by 
coughing. 

Morphine Derivatives. — Although these therapeutic effects may be 
obtained by the use of morphine in proper doses (3-10 mg. for adults, 
correspondingly smaller doses for children), still its other effects, such 
as constipation or, in nervously susceptible patients, excitement, as 
well as the danger of opening the door to the readily acquired habit in 
chronic sufferers, such as tubercular patients, are ample reasons for 



340 PHARMACOLOGY OF THE RESPIRATION 

avoiding as long as possible the use of this drug for the relief of 
cough. This is the more feasible as certain derivatives of morphine 
do not possess the disadvantages mentioned [in the same degree. — Tr.], 
while they produce the desirable effects on the respiratory function 
in even higher degree {Heinz, Dreser, Frankel). Of these derivatives 
the following are of practical importance: 

1. Codeine, a methylmorphine, best administered as codeine phos- 
phate, which is readily soluble in water. It may be used several times 
daily in doses of 0.04-0.06 gm. for adults (0.1 gm. maximal single 
dose, 0.3 gm. maximal daily dose). Smaller doses, even when fre- 
quently repeated, are of slight efficiency and are not to be recom- 
mended (Frankel). Habituation need not be feared, even in case 
of use for months or years. 

2. Dioxin, ethylmorphine hydrochloride, in its actions, is very 
similar to codeine, but it appears to be more powerfully analgesic and 
constipating, although neither of these actions is as pronounced 
as with morphine. It may be administered orally or subcutaneously in 
doses of 0.015-0.03 gm. 

3. Peronin, benzoylmorphine hydrochloride, 0.02-0.04 gm. per 
dose. [Is little used. Resembles dionin. — Tr.] 

4. Heroin, diacetylmorphine hydrochloride, which is readily soluble 
in water, diminishes the excitability of the respiratory centre more 
strongly than the other morphine derivatives, and even in small doses 
slows and deepens the respiration. It is in general more like morphine 
than the other derivatives mentioned, and in children produces a 
strong narcotic effect (see p. 38). For adults the dose.is 3-5 mg., for 
children over one year y 2 mg., under one year % mg. With this drug 
there is danger of habit formation. 

Still other substances exert a sedative action on the respiratory 
centre, as, for example, camphoric acid, an otherwise but slightly 
active oxidation product of camphor. Dose, 1.0-2.0 gm. It may be 
administered in alcoholic solution (Heinz and Manasse). 

BIBLIOGRAPHY 
Dreser: Verb. d. Ges. d. Naturfr. u. Aerzte. Aachen, 1900, vol. 2, p. 26. 
Dreser: Pfliiger's Arch., 1898, vol. 72. 
Frankel, A.: Miinchn. med. Woch., 1899, No. 46. 
Frankel: Miinchn. med. Woch., 1899 3 No. 24. 
Heinz: Diss., Bonn., 1890. 

Heinz u. Manasse: Deut. med. Woch., 1897, No. 41. 
Loewy, A.: Pfliiger's Arch., 1890, vol. 47, p. 601. 
Loewy: Respiration u. Circ, Berlin, 1895. 
Loewy: Pfliiger's Arch., 1894, vol. 58, p. 416. 
Reach u. Roder: Biochem. Ztschr., 1909, vol. 22, p. 471. 

EMBARRASSMENT OF THE RESPIRATION 

Excluding such conditions as compression of the lungs by air or 

fluid in the pleural cavity and those where the respiratory muscle 

is mechanically incapacitated, — for example, spasm or paralysis of 

the diaphragm, — inefficient breathing may be due to a reflex inhibition 



EMBARRASSMENT OF THE RESPIRATION 341 

of the thoracic movements by pleuritic pain, intercostal neuralgia, etc., 
to an abnormal condition of the air-passages, or, finally, to a disturb- 
ance of the pulmonary circulation. Only these last three causes may 
be affected by medicinal treatment. 

1. Pain may interfere with the movements of the thorax on one 
or both sides. This may be experimentally demonstrated in animals 
or in man by applying mild irritants, such as mustard plasters or 
tincture of iodine, to one or both sides. The precordial region appears 
to be by far the most susceptible portion of the thorax, and particu- 
larly so to irritation by mustard plasters (L. Mayer). As a result 
of such irritation the breathing becomes shallower and slower, espe- 
cially in its inspiratory portion, while the unirritated side compen- 
sates with increased movement. Such irritation of the healthy side 
may be occasionally carried out for therapeutic purposes in order to 
bring about freer movement of a lung which has become more or less 
inactive as a result of pleuritic adhesions or other pathological 
processes. 

If the counterirritation be very powerful, — as, for example, that 
caused by the thermocautery, — the movements of the side where the 
irritation is applied, although becoming slower, do not become less 
extensive, but, on the contrary, marked deepening of inspiration 
occurs, which may last for some time after the active irritation has 
ceased. Similar favorable effects of slowing and deepening of the 
respiration may result from milder counterirritation — by tincture of 
iodine — in case the breathing has been shallow and rapid as a result 
of spontaneous pain, such as that occurring in pleurodynia, for such 
mild irritations have some local anaesthetic action. By such means the 
respirations of the patient may be relieved and improved (see p. 34). 

In inflammatory conditions of the mucous membrane of the 
respiratory tract, drinking or gargling with emollients, such as 
althea or mucilage of acacia, may give relief by their effects on irritant 
reflexes. 

2. Impairment of the respiration as a result of obstructions in the 
respiratory tract may occur as a result of an inflammation, on account 
of excessive viscid bronchial secretion, or as a result of spasmodic 
closure of the air-passages. 

Vasoconstricting drugs and those lessening secretions may be 
used with advantage in inflammatory conditions in the lungs with 
congestion of the mucous membrane and profuse secretions. The best 
ones to use are volatile substances such as turpentine and other vola- 
tile oils, which may be atomized or inhaled, or, especially in chronic 
conditions, inhaled in steam. Their deodorizing and antiseptic effects 
may here be of some value by limiting putrefaction. This is espe- 
cially the case when true antiseptics, such as balsam of Peru, thymol, 
creosote, etc., are inhaled, fit has always appeared questionable 
whether such substances when thus used actually reach the inflamed 



542 PHARMACOLOGY OF THE RESPIRATION 

structures in amounts large enough to exert any appreciable antiseptic 
actions. The undoubted favorable actions observed clinically would 
appear to be better explained by their local annesthetic and vascular 
actions. — Tr.] 

Quite often the indication is to render the secretions more fluid 
and to facilitate their removal, — i.e., to cause expectoration. This is 
the case when the secretion is very scanty or when, although profuse, 
it is extremely viscid, so that it is only with difficulty expelled by 
the actions of the ciliated epithelium or by coughing. Clinical 
experience indicates that the so-called expectorants often fulfil this 
indication more or less satisfactorily. 

EXPECTORANTS 
From the experimental side little is known of the manner in which 
expectorants act. 

The experiments of Henderson and Taylor and those of Rossbach and Calvert, 
which latter two are open to many objections, are practically the only ones 
dealing- with this subject. 

As stated by Purhinje and Valentin in 1834, the ciliary movements of the 
cells of the bronchial mucous membrane are of great importance for the removal 
of mucus, especially from the smaller bronchi, in which coughing cannot produce 
any effective acceleration of the movements of the air. However, according to 
Engclmann, a very tenacious thick coating of mucus opposes an insuperable 
obstacle to the ciliary movements, and only when the secretion has become 
thinner and more fluid are these cells able to resume their function, provided 
that they have not lost their excitability and are still able to perform them, which 
is not always always necessarily the case in inflammations of the bronchial 
mucous membrane. 

It is not known whether or not the ciliary movements may be stimulated 
by the expectorants, although Virchoio in 1854 observed an active excitation of 
the previously motionless cilia after a direct application of potassium or sodium 
hydrate to the human tracheal mucous membrane, while strong ammonia stopped 
the movements without any primary stimulation. These two observations are, 
however, of no significance for estimating the effect of medicines, but perhaps 
those of Engclmann on the pharyngeal mucous membrane of the frog may be of 
some significance. According to this author, very small quantities of C0 2 , ether, 
and ammonia stimulate the ciliary movements, while larger amounts depress them. 

The unstriped bronchial muscles appear to play a decidedly more important 
role in the transportation of mucus from the alveoli and bronchioles up into the 
larger branchi, for there is no ciliated epithelium in the alveoli and the terminal 
bronchi. Both the alveoli and the bronchi contain unstriped muscles, whose chang- 
ing tone is controlled by constricting and dilating nervous impulses which reach 
them through the vagus. This innervation, and, as will be seen later, also the 
pharmacological reaction of the bronchial muscles, is very analogous to the con- 
ditions in the intestine, and it is very possible that these organs also are capable 
of ascending peristaltic movements. In this fashion lumps of mucus might be 
moved upward in the narrowest bronchi (Gerlach). Einthouen observed spon- 
taneous rhythmic contractions of the bronchial muscular apparatus independently 
of any nervous inlluence, but he did not conduct any investigation to determine 
whether these were always simultaneous contractions of the whole system or 
whether they were alternating peristaltic movements. It is not improbable that 
such peristalsis may be accelerated or strengthened under the influence of some 
of the expectorants. 

Salts as Expectorants. — All the salts of the sodium chloride 
group (see section on salt action) may exert some expectorant action 
and increase the secretion of mucus, for they are in part excreted 



EXPECTORANTS 343 

by the bronchial mucous membrane and thus may bring about the 
secretion of an increased quantity of water and (as occurs whenever 
secretion is increased) of alkaline carbonates. This increased alkalin- 
ity of the secretion would be accompanied by a diminution of its 
viscosity, for the tenacity of the mucus is diminished as its alkalinity 
rises. In practice some of these salts are much used for this purpose. 
Among these are sodium chloride (the waters of Wiesbaden and 
many other springs) and potassium iodide or potassium sulphocya- 
nide, which is not harmful in thyroid disease. (Seep. 400 for dangers 
of KI in thyroid patients.) 

Ammonium chloride appears to be still better for this purpose, for, 
following its administration, traces of ammonium carbonate are 
perhaps formed in the bronchial mucous membrane, and this has a 
special power of liquefying mucus and stimulating the ciliary move- 
ments. Its use in combination with soothing licorice preparations 
may therefore be understood. The alkaline carbonates in Ems water 
and many other mineral waters act in a similar fashion. 

NAUSEANT EXPECTORANTS 

Besides the salts mentioned, emetic drugs, especially apomorphine, 
ipecac, and antimony salts, produce a similar stimulation of the bron- 
chial secretions when they are given in small non-emetic doses (see 
p. 179). This is probably a symptom of the first stage of their emetic 
action, which causes the striking increase of secretions which accom- 
panies the nausea induced by larger doses. With apomorphine the 
action is a direct one, with ipecac, antimony, etc., a reflex one, on the 
centres controlling the secretion of the bronchial mucous glands, 
for these glands are affected readily, and often, especially in children, 
even more readily than are the sweat-glands, by drugs like pilocarpine, 
which are specific secretory excitants. 

Moreover, inasmuch as with more pronounced emetic action the 
vagus innervation controlling emesis is excited, it may be that, in the 
first stages of their action, this vagus stimulation may cause the peri- 
stalsis in the smaller bronchi to become more active. This may at 
least be considered as possible. 

Apomorphine hydrochloride in corresponding dosage appears to 
act more promptly and energetically than ipecac or antimony, but its 
action seems to be less lasting. It may be given several times daily 
to adults in doses of 2-10 mg. Alkalies should be avoided when this 
drug is prescribed. 

Ipecac may be administered in various forms in dosage of 0.05 
to 0.2 gm. to adults and 0.01-0.1 gm. to children. It is often combined 
with opium for the purpose of relieving a harrassing cough, but it is 
questionable whether this combination is a good one, for presumably 
morphine will depress the bronchial peristalsis I Brodie and Dixon). 

Antimony and potassii;m tartrate, 2-10 mg. several times daily, 
may irritate n susceptible stomach mucous membrane. This is not 



344 PHARMACOLOGY OF THE RESPIRATION 

likely to occur if the sulphate of antimony be used, for this prepara- 
tion is entirely insoluble in water, and in the acid gastric juice is 
changed only gradually into the active antimony oxide (see Emetics). 
Senega and quillaja bark act as expectorants in a fashion not 
clearly understood, but in both saponins are considered to be the 
effective constituent. According to Henderson and Taylor, senega 
produces expectoration reflexly by its action on the stomach, as do 
ipecac, tartar emetic, and ammonium chloride. 

Saponin is a name given to a large number of non-nitrogenous substances 
occurring especially in the bark and roots of numerous plants. They are charac- 
terized by their glucosidal nature and by their property of aiding in the formation 
of soapsuds, and are mixtures of various substances which are chiefly colloidal 
and which have not yet been chemically defined (quillaie acid, sapotoxin, sar- 
saparin, parillin, etc.). As a general rule, they are strongly cytotoxic and, when 
injected subcutaneously, intensely irritating. When injected intravenously, they 
cause haemolysis, severe inflammation, enteritis and depression of the central 
nervous system. The epithelium of the mucous membrane of the alimentary 
canal is, "however, very resistent to saponin and completely prevents saponin 
poisoning, as it does not permit the passage of altered saponins into the blood. 

The resistance of the epithelial cells to saponin has been especially well 
demonstrated by Lhomme's observation that the ciliary movements in the frog's 
oesophagus were not disturbed by the application of concentrated solutions of 
saponin, even in the course of hours. The only effect on the mucous membranes, 
therefore, is a slight irritation of their sensory secretory mechanism. Tickling 
and increased secretion of mucus and saliva occur when these substances are 
taken into the mouth and throat. It is not known whether the increase of 
bronchial secretion is due to reflex action produced in this way or whether it is 
caused by an increase tendency to clear the throat or to cough. Calvert found 
that the* bronchial secretions were inhibited after the intravenous injection of 
saponin, but such an experiment is not at all adapted to explain the therapeutic 
effect of saponin taken by mouth, for, when thus administered, it does not pass 
into the blood. 

Theoretically it is of interest that the toxic action of saponin on the red 
blood-cells, and probably also on other animal cells (Ransom), is explained 
by its chemical affinity for cholesterin, the constituent of the cells which is 
chemically affected by the saponins. After saturation with cholesterin, saponin 
is no longer toxic to the red blood-cells, and consequently the blood-plasma, 
which normally contains a certain amount of cholesterin, protects the red cells 
against a limited amount of saponin. 

BIBLIOGRAPHY 
Brodie and Dixon: Journ. of Physiol., 1903, vol. 29, p. 97. 
Calvert: Journ. of Physiol., 1896, vol. 20, p. 158. 
Einthoven: Pfliiger's Arch., 1892, vol. 51, p. 307, lit. here. 
Engelmann: Hermann's Hdb. d. Physiol., 1877, vol. 1. 

Henderson and Taylor: Journ. of Pharmacol, and Exp. Ther., 1910, vol. 2, p. 153. 
Kopke: Dissert., Greifswald, 1899. 
Lhomme, M. J.: These Paris, 1883. 

Mayer, L. : Trav. de l'institut Solvay, 1891, vol. 4, here lit. 
Ransom: Deut. med. Woch., 1901, No. 13. 
Rossbach: Berl. klin. Woch., 1882, Nos. 19, 20, 27. 
Rossbach: Wiirzburger Festschr., 1882, vol. 1, p. 85. 

PARALYSIS AND SPASM OF THE GLOTTIS 
Normal functioning of the glottis is necessary for normal respira- 
tion. In paralysis of this organ a valve-like closure of the vocal cleft 
may occur during inspiration, while, in spasm of the glottis, it is 
self-evident that closure of the vocal cleft will prevent both inspira- 



EXPECTORANTS 345 

tion and expiration. Except opium or morphine, which as a rule 
relieve spasm in catarrhal laryngitis or croup, we know of no pharma- 
cological agents which will directly affect the laryngeal muscles and 
which are able to relieve their spasmodic contractions. 

BRONCHIAL SPASM 

Another obstruction to the ventilation of the lungs may result 
from spasm of the bronchial muscles, usually associated with the 
so-called asthma nervosum, which probably in most cases is due to 
an abnormally increased reflex excitability of the bronchial vagus 
centre (Brodie and Dixon). This reflex may be excited by stimuli in 
the sensory nerves of diseased bronchial, tracheal, and nasal mucous 
membranes. As a result of the spasmodic contraction of the smaller 
bronchi, the lungs become abnormally distended or inflated, for in 
inspiration the pressure of the atmosphere can still overcome the 
increased resistance, but in extirpation the limited elasticity of the 
lungs and the pressure of the expiratory muscles are not sufficient to 
do this. Therefore the quantity of residual air must increase with 
each respiration. 

TREATMENT OF ASTHMA 

Such an asthmatic attack may be relieved either by blunting the 
excitability of the central reflex mechanism — for example, with chloral 
hydrate or similar drugs * — or by depression of the vagus nerve- 
endings in the bronchial muscles. This latter effect may be induced 
by inhalation of ether or chloroform, as Brodie' s and Dixon's experi- 
ments on animals clearly showed, but this has not been therapeutically 
attempted [? Tr.]. Bronchial spasm may often be satisfactorily 
relieved by drugs having the specific power of rendering the vagus 
nerve-endings — unfortunately, not only in the lungs — unexcitable. 

The alkaloids of the atropine group, and lobeline, which 
closely resembles nicotine in its actions {Edmunds), are the best of 
these. According to Brodie and Dixon, the action of atropine is more 
lasting than that of lobeline. 

Since the middle of the last century, stramonium leaves, bella- 
donna, hijnsci/aiints, and lobelia have been recommended as remedies 
for various spasmodic affections, and especially for bronchial asthma. 
Extracts of these drugs and the smoke of their smouldering leaves 
or the salts of atropine have all been employed for this purpose. If 
asthma cigarettes exert any curative action, it must be due to the 
small quantities of atropine salts f which are carried along mechani- 
cally in the inhaled smoke and thus reach the pharynx and lungs 
I ////•// a. N< tolitzhy I. 

* Urcthan is stated by Brodie and Dixon (loc. cit.) to relax the bronchial 
muscles by a direct action on them. If this be correct, the drug should I"' a 
Useful asthma remedy, f<»r its hypnotic action is comparatively Blight. 

t According to (Hintlirr, tin- smoke of a. cigarette containing 4.0 gin. of 
Btramonium leaves contains 0.4 tag, of atropine. 



346 PHARMACOLOGY OF THE RESPIRATION 

Atropine (1/20-^ mg. several times a day), which is contained 
in the iirst three drugs mentioned and its congeners (see Atropine 
group, p. 154), as also lobeline, from Lobelia inflata (Indian tobacco), 
possess the physiological property of depressing the motor nerve- 
endings of the vagus in the lungs, so that the bronchial muscles relax 
and the dilated bronchi no longer present an abnormal resistance to 
the expired air. As at the same time these drugs stimulate the respira- 
tory centre (Drcser), a marked improvement and strengthening of the 
respiration follow their administration. 

In addition, excessive bronchial secretion, which often plays a 
part in exciting attacks of asthma, is lessened by these drugs. When, 
however, sudden vasomotor disturbances, such as congestion of the 
bronchial mucous membranes, are responsible for the attack, — as, for 
example, in the asthma of hay fever, — these drugs, as may be well 
understood, are without effect. [As a matter of fact, the asthma in 
hay fever is probably due, in part at least, to spasm of the bronchial 
muscles, which may be secondarily caused, and clinical experience 
has demonstrated that marked relief is often obtained by the use of 
atropine or similar drugs in asthma of this type. — Tr.] 

It is claimed that opium smoking and the inhalation of the smoke 
from smouldering paper impregnated with saltpetre are of value in 
bronchial asthma. Such smoke contains varying quantities of car- 
bonates and nitrites in addition to the usual gases present in smoke. 
Under some conditions a favorable influence may be expected from 
the nitrites, but this will hardly be the case in bronchial asthma, 
the condition now under discussion. This will be more likely to 
occur in angina pectoris, which is occasionally mistaken for bronchial 
asthma. [Here again clinical experience is not altogether in accord 
with the opinion of the author. The translator is confident that he 
has occasionally, though rarely, seen unmistakable relief secured by 
the use of nitrites in cases of undoubted bronchial asthma. — Tr.] 

[Epinephrine — The marked relief following the subcutaneous in- 
jection of epinephrin (0.5-0.7 mg.) in asthma is so striking and well 
known that it should be mentioned here. Plethysmographic experi- 
ments, completed in 1911 in the laboratory of H. Meyer, demonstrate 
that this drug causes an excitation of the sympathetic nerve-endings 
here just as in other organs (see p. 141) and produces a relaxation of 
the bronchial muscles. A number of blood-pressure observations made 
on such patients, by the translator and by I. I. Lemann, have shown 
that the relief of the asthmatic attack following the injection of 
epinephrin is not necessarily accompanied by any rise in the blood- 
pressure. As a matter of fact, the blood-pressure occasionally rises, 
but more often remains constant or falls. The fall in blood-pressure, 
when it does occur, is apparently due to the relief of the dyspnoea 
and cyanosis. It has been claimed by various authors that the oral 
administration of epinephrin also affords relief in asthma. The trans- 
lator from his own experience can, however, report only failures to 



EXPECTORANTS 347 

confirm these statements. In a number of cases, after oral adminis- 
tration had failed to give any relief, the subcutaneous administration 
promptly stopped the attack. Unfortunately, in several of the author's 
cases, after frequent repetition of the administration during a num- 
ber of months, the treatment became ineffectual. — Tr.] 

[Iodides. — Xo discussion of the pharmacology of asthma or bronchial spasm 
is complete which does not include some consideration of the action of iodides 
in these conditions. Clinical experience has demonstrated that in a large pro- 
portion of cases of true bronchial asthma the daily ingestion of fifteen to thirty 
grains of iodide of potash results in a more or less pronounced and unmistakably 
beneficial effect on the frequency of the attacks. While some of this benefit 
might be explained as the result of the expectorant action of the iodide (see 
p. 343), there is another probable explanation of it which, as far as the 
translator has been able to learn, has not yet been suggested. As will be dis- 
cussed later (p. 354 ft'.) the thyroid gland exerts an active effect on the sympathetic 
system, perhaps in the sense that it acts as a hormone on the chromaffinnic 
organs. Further, it is established that, at any rate under many conditions, the 
administration of the iodides causes an increase in the functional activity of 
the thyroid. Consequently it appears at least plausible that the favorable effects 
of the regular ingestion of iodides are to be attributed to an increased sympa- 
thetic tone brought about through increase of thyroid function. Otherwise ex- 
pressed it might be stated that the daily use of iodides may in this respect have 
similar effects to the constant administration of minimal doses of epinephrin, 
which we have just seen is a most efficient means of relieving the condition of 
bronchial spasm. A further pharmacological deduction would, be that possibly 
the administration of thyroid substance would be a more direct way of attaining 
this end.— Tr.] 

BIBLIOGRAPHY 

Brodie and Dixon: Transact. Pathol. Soc, London, 1903, vol. 54. 

Dreser: Arch. f. exp. Path. u. Pharm., 1890, vol. 26, p. 237. 

Edmunds: Amer. Journ. Physiol., 1904, vol. 11, p. 79. 

Einthoven: Pfliiger's Arch., vol. 51. 

Giinther: Wien. klin. Woch., 1911, p. 748. 

Hirn u. Netolitzky, Wien. klin. Woch., 1903, p. 583. 

3. Disturbance in the circulation in the lungs, such as stasis re- 
sulting from cardiac insufficiency, may markedly interfere with the 
respiration and cause dyspnoea. The blood accumulating in the 
pulmonary capillaries distends them and causes rigidity of the lungs 
(v. Basch's "Lungenstarre"), the power of excursion of the lungs 
being diminished so that the renewal of air is seriously interfered 
with. The increased C0 2 tension in the blood-vessels resulting from 
this condition, then in its turn causes subjective dyspnoea with violent 
but ineffectual attempts to breathe. In cases of cardiac insufficiency 
the respiratory disturbances may be relieved by the relief of the 
disturbances of compensation resulting from the administration of 
drugs of the digitalis group. 

The acute dyspnoea of exertion, such as occurs with healthy 
hearts after running, mountain climbing, etc., may be prevented 
by small doses of caffeine, 0.25 gm., taken about two hours before- 
hand * Parisot). 

BIBLIOGRAPHY 

v. Basch: Arbeiten, 1892 and 1890, vols. 2 and 3. 
Parisot: These de Paris. 1890. 



CHAPTER X 

PHARMACOLOGY OF THE RENAL FUNCTION 
PHYSIOLOGY OF DIURESIS 

The renal secretion of the healthy mammal is an albumen-free, 
dilute aqueous solution of the products of metabolism and of sub- 
stances which after penetrating into the body are not utilized or 
retained but simply pass through it. 

Available Water Necessary for the Secretion op Urine. — The 
first condition necessary for the formation and excretion of urine is the 
presence of available water, — i.e., water which may be given up by the 
blood. As the normal water content of the blood is retained with 
great tenacity, it is essential that there be a certain, although slight, 
excess of water in the blood, a temporary hydremia, if the giving up 
of water — i.e., diuresis — is to occur. 

In the blood-plasma the water is combined with its dissolved crystalloids 
and with colloids (proteids) in a state analogous to that of the " Quellungs " 
water, i.e., intramolecularly imbibed water, in a gel or jelly. Just as in a 
jelly, a certain portion of the " Quellungs " water of the blood may be readily 
squeezed out by pressure. As, however, the concentration of the proteid increases 
the tenacity of the combination between the water and the proteid, the " Quel- 
lungs " pressure, rapidly rises, and very quickly becomes so great that even the 
highest pressure possibly available in the kidney can squeeze no water out of 
the blood. Superfluous water, introduced with food or entering the blood from 
the various cavities of the body and from the tissues, is under ordinary conditions 
readily excreted. In case these sources fail to supply extra water, a very small 
portion of the water normally present in the blood may be excreted, but the 
kidneys can under no conditions excrete what remains. 

Importance of Sufficient Blood-pressure. — It may be considered 
as established that the water of the urine is excreted chiefly in the 
vascular loops of the glomeruli. For this to occur, the blood-pressure 
in them must be sufficient to overcome not only the hydrostatic pres- 
sure in the uriniferous tubules and ureters, but also the combination 
between the water and the dissolved colloids, the "Quellungs" pres- 
sure, of the blood-plasma. Under normal conditions, according to 
Starling, this equals about 30 mm. Hg, and, as a matter of fact, 
urinary secretion usually ceases when the blood-pressure falls much 
below 40 mm., and, within physiological limits, increases almost pro- 
portionately with the rising blood-pressure (Goll). (See Fig. 40.) 

If, on the other hand, the blood is artificially made markedly 
hydremic, its "Quellungs" pressure becomes low or practically 
zero. This occurs, for example, during the continuous intra- 
venous infusion of isotonic sodium chloride solution, and under 
these conditions water may be secreted in the urine with a minimal 
348 



PHYSIOLOGY OF DIURESIS 



349 



"blood-pressure, which is just sufficient to maintain the blood flow 
(Gottlieb it. Magnus). The process is therefore fundamentally com- 
parable to a filtration or a transudation. 

THEORY OF URINARY SECRETION 

This conception forms the essential portion of Ludic-ig's theory of urinary 
excretion, and was first deduced by Bowman from anatomical facts and later by 
Liidicig from the above-mentioned experimental data. According to it, in the 
glomeruli there is expressed from the blood a " colloid-free " filtrate containing 
water and dissolved crystalloids such as urea, salts, etc. As this passes down 
through the uriniferous tubules it undergoes a concentration, the water being 
reabsorbed into the blood by osmotic action, which flows from the glomeruli to 
the thick network of capillaries surrounding the tubules. 

On account of a number of objections, Heidenheim has offered, as a substi- 
tute to this essentially mechanical conception, the so-called secretion theory, 
according to which the water is not expressed from the blood as a result of pres- 
sure, but is secreted by a specific cell activity, while the solid constituents are 
actively secreted by the epithelium of the uriniferous tubules in a manner 
analogous to that in which the secretion of other true glandular epithelium 




Fig. 40. — VS =vagus stimulation; F=venesection; 7=infusion of blood; C=closure, and 
0= opening of the carotid and crural arteries. Urinary excretion in dog under varying blood- 
pressure (Go//). 



Heidenheim's conception provides without difficulty for all the phenomena 
observed in normal and altered renal secretion, explaining everything by an 
adaptation of the kidney to the needs of the organism. It renounces, however, 
any attempt to analyze the process, and especially any attempt to differentiate the 
influence which may be exerted on the excretion of urine by varying physiological 
or pathological conditions. Such are, for example, the effect of diuretics, such as 
the salts, calomel, caffeine, etc. 

I In- functional processes of all other glands of the body are independent of 
direct physical and of almost all chemical inlluences. They are specilic processes, 
directly or rellexly under nervous control, and may be analyzed chiefly in respect 
to their dependence on nervous control. On the other hand, we know of no 
specific innervation for the kidney, but we do know that there are certain physical 
factors, dependent on the composition of the blood and on its circulation through 
the kidneys, which are of decisive importance for its activity. 

However, the investigations of the last decade have clearly shown 
that l he formation of the urine cannot yet be completely or evi n in 
greater part explained physicochemically. 



350 PHARMACOLOGY OF RENAL FUNCTION 

It will therefore he our task to find out how far we may follow, or 
recognize as possibly effective, the influence of physical-chemical fac- 
tors on the secretion of urine under abnormal conditions {for example, 
alt (ration of the renal circulation), and especially on the alterations 
of function resulting from the action of pharmacological agents, and 
to learn how far on the other side we must assume specific secretory 
processes which are not susceptible to further analysis. 

The Importance of the Amount of Blood Flowing through the 
Kidney. — If the blood flows slowly through the glomerular vessels (on 
account of low pressure or decided resistance), or should it stagnate 
there, — as, for example, when the renal veins are ligated, — the secre- 
tion of urine ceases, even though, in the later case, the pressure in the. 
glomerular loops must rise to its maximum. This fact was especially 
brought forward by Heidenheim as an objection to the theory of 
pressure filtration and advanced as an argument for the correctness 
of the secretory theory. However, the filtration theory demands, be- 
sides an adequate blood-pressure, that the blood flow in these vessels 
shall be rapid enough to supply to them constantly fresh blood in 
sufficient quantities, for otherwise the blood, stagnating in the glome- 
ruli, must, on account of loss of its available water, necessarily in- 
stantly become so concentrated that its "Quellungs" pressure will 
rise so high that, even under any attainable blood-pressure, no appre- 
ciable amounts of water may be expressed, and the secretion of urine 
must therefore cease. Diuresis, therefore, under all conditions de- 
mands an adequately rapid changing of the blood in the glomerular 
vessels, — i.e., an adequate circulation of blood through the kidneys. 
It is apparent that this factor is of even greater moment for diuresis 
than is the blood-pressure. 

Excretion of Urea, NaCl, etc., in the Glomeruli. — Most of the 
crystalloids dissolved in free form in the blood do not cause any 
appreciable osmotic resistance to the passage of the urinary fluid 
through the walls of the glomeruler loops (see p. 384 ff.), and therefore 
do not hinder the excretion of water. On the contrary, diuresis 
generally increases when larger amounts of these substances are con- 
tained in the blood (Tamman) . From this it is necessarily deduced 
that these substances are excreted in the glomeruli together with, and 
at the same time as, the water (Hermann, Treskin, Richet, Loewi, 
Magnus). As a matter of fact, their excretion rises and falls almost 
proportionately with the amounts of water excreted, they being appa- 
rently swept along with it. 

Pathological Retention of Salts. — However, what has been said 
above is subject to an important limitation, for in experiments on 
animals it has often been observed that, in long-continued experiments 
in which intravenous saline infusion has been given to cause diuresis, 
the diuresis after a time diminishes and the kidney retains more and 
more, not only of the water but also of the sodium chloride infused. 



PHYSIOLOGY OF DIURESIS 351 

Moreover, it is well known that in certain pathological conditions in 
man, chlorides are very sparingly excreted, and that the administration 
of salt, instead of increasing diuresis as it does normally, actually 
decreases it (Widal and J aval, Griiner, Schlayer, Hading er and 
Takayasen, and a review in v. Noorden's Pathology of Metabolism, 
vol. 1). 

Impaired Permeability of the Glomerulus. — In order to understand 
this phenomenon we must, in our consideration of the nitration theory, 
add to it the almost self-evident premise that the permeability of the 
living filter membrane in the glomeruli for free crystalloids or ions is 
neither unchangeable nor without limitation, but that, on the contrary, 
the size of the hypothetical pores changes under different nervous, 
mechanical, or direct chemical influences, and that therefore many 
substances in solution can pass through them, sometimes more and 
sometimes less readily and sometimes not at all. 

It is well known that the permeability of this membrane for proteid is subject 
to variations. Under normal conditions proteid does not pass through the human 
kidney in appreciable amounts, but under certain conditions very slight changes 
in the circulation are sufficient to render the glomeruli permeable to albumen. 
This occurs, for example, in orthostatic albuminuria (Jehle). Moreover, experi- 
mental analogies for the variable permeability of niters are not lacking. For 
example, filters impregnated with gelatin are rendered more or less permeable 
for different substances, according to the gelatin concentrations used {Bechhold) . 

Secretion by the Tubular Epithelium. — While the excretion of 
many of the soluble constituents of the urine in general occurs as a 
result of physical phenomena, it is known that the secretion of some 
other substances, among them uric acid and many salts of the heavy 
metals, occurs in a different fashion and does not appear to stand 
in any recognizable relationship with the amounts of urine excreted. 
Apparently they are excreted by the functional activity of the epi- 
thelium of the tubules. Their secretion must therefore be considered 
as due to a secretory activity incapable of closer analysis, just as is 
the case with secretions in other true glands. 

Concentration of the Glomerular Filtrate. — The urine flowing from 
the kidnej' is usually more concentrated than a true filtrate from 
the glomeruli could possibly be. This higher concentration is, how- 
ever, readily comprehensible if in the secretory theory it is premised 
that the solid constituents of the urine, including urea and the salts, 
are secreted by the uriniferous tubules and mixed in with the dilute 
glomerular filtrate. As qualitatively and quantitatively this secretion 
is constantly changing with the needs of the organism and the momen- 
tary condition of the secreting cells, a varying composition of the 
urine is to be expected. As, however, as was mentioned above, the 
crystalloids appear in the urine in quantities nearly proportional to 
the amounts of water, and as their excretion by physical means (such 
as filtration or transudation in the glomeruli) may be considered as 
established, it would be necessary to assume the occurrence of an 



352 PHARMACOLOGY OF RENAL FUNCTION 

additional secretion of the same crystalloids by the epithelial cells of 
the tubules in order to bring about the final concentration. This com- 
plicated hypothesis need, however, not be adopted if it be assumed 
that the concentration of the urine is brought about by a reabsorption 
of water, similar to that which takes place in the large intestine 
during the concentration of its liquid contents. 

In the human alimentary canal about 4000 e.c. of water are secreted in every 
24 hours, and of this about 3900 c.c. are reabsorbed. In order to secrete about 
30 gm. of urea in 24 hours, 50 litres of fluid must be filtered in the glomeruli 
from blood containing about 0.6 per cent, of urea, and of this about 48 litres must 
be reabsorbed in the long, sinuous course of the uriniferous tubules. Between 
500 and 600 litres of blood flow through the kidneys in 24 hours, of which about 
one-tenth would have to be expressed as a filtrate to satisfy the Ludwig hypothesis, 
There is nothing improbable in such an assumption. On the contrary, the 
appreciably narrower lumen of the vas deferens as compared with that of the 
vas afferens may be considered as a proof that a considerable portion of the 
fluid of the blood-plasma entering the glomenilus is removed in some fashion, — 
in other words, is excreted. 

Selective Reabsorption. — The reabsorption of water in the tubules 
cannot be explained physicochemically any more than that of certain 
of its crystalloid constituents. However, numerous earlier investiga- 
tions * rendered it probable, while the most recent observations 
(Nishi) have certainly proven that the tubules are able to absorb not 
only water but also dissolved substances, especially the readily dif- 
fusible crystalloids. 

The normal urine of rabbits and dogs contains no recognizable amounts of 
sugar. In accordance with this, Nishi found that normally the medullary portions 
of the kidney contained no sugar, while it was constantly present in the cortical 
portion, but, if in any fashion glycosuria were induced, sugar was found in the 
medullary portions. Inasmuch as the minimal amounts of sugar contained in 
the blood could not influence the quantitative determination of the sugar present 
in kidneys from which the blood had been thoroughly removed, these observations 
permit the conclusion that sugar is excreted in the cortex, but that under normal 
conditions it disappears again in the medulla and that it is reabsorbed there. 
Only when larger amounts are excreted in the glomeruli and when the reabsorp- 
tion is incomplete does sugar appear in the urine (Pollak). 

Combined Effect of Filtration, Secretion, and Reabsorption. — 
In any case it may be maintained that, generally speaking, the extent 
of the filtration taking place in the glomeruli determines the total 
quantity of the urine secreted, while the momentary composition of 
the urine is determined by a selective secretion or reabsorption in the 
tubules. 

Secretion of Water by the Tubules. — In addition to this power of 
free absorption, the tubules probably also possess the faculty of excret- 
ing water under some conditions and adding this to the glomerular 
filtrate. This would appear to be analagous to the behavior of the 
sweat-glands, which also excrete almost pure water in amounts which 
vary according to their blood supply and the water content of the 

* v. Kobicranski, Halsey and Meyer, Cushny, Loeioi, Gottlieb and Magnus, 
Griinicald, Sollmann : see latter for lit. 



PHYSIOLOGY OF DIURESIS 



353 



blood. The secretion of a very dilute urine, the osmotic concentration 
of which does not equal that of the blood, which is observed after free 
drinking of water, in diabetes insipidus, etc., can hardly be explained 
on any other assumption {Frey). Moreover, there can be no doubt 
that there is a certain antagonism in the behavior of the capillary 
system of the glomeruli, which is supplied by the vasa afferentia 
of the renal artery, and the capillary system of the tubules, which 
receive their supply from the vasa efferentia and the arteriole recta3. 
If the vasa afferentia dilate, the vasa efferentia, and perhaps also the 
arteriolse recta?, contract. Thus the pressure and flow in the glome- 
ruli are increased while in the tubular capillaries they are relatively 
diminished, and vice versa. In accordance, therefore, with such varia- 
ble conditions, filtration in the glomeruli or secretion in the tubuli 
may preponderate (see Fig. 41). 

It is self-evident that both of these vascular systems are, like all 
other blood-vessels, under the control of the nervous system, but 
we have little exact knowledge of this mechanism. The oncometric 
determination of the volume of the kidney serves as a means of esti- 



Glomerular 

capillaries 

I 
Vasa/fer. /Zp^>\. Vas efler. 



To Vena renalis 




ArleriolarecS. 

Fig. 41. 

mating the blood flow through it, if the outflow of venous blood 
and of urine be unhindered. Further, the color of the venous blood 
allows an approximate estimation, for with increased blood flow the 
blood appears light red through the wall of the vein, while with dimin- 
ished blood flow the blood appears darker. 

According to Tif/rrstedt, during moderate diuresis blood amounting to 80 
per cent, of the kidney weight flows through it in one minute; with greater 
diuresis as much as 140 per cent. If both kidneys weigh 300 gm., this would 
amount in man to 345-600 kg. in 24 hours. 

BIBLIOGRAPHY 

Bechhold: Ztschr. f. phys. Chem., 1907, vol. 00. 
Butschli: Bau quellbarer Etfrper, etc., LS!)(J, p. 24. 
( lushnj : Journ. of Phys., 1!)01, vol. 27. 
Prey : ' Pfltiger'a Arch., 1906, vol. 112. 
Frey: Pfltiger'a Arch., 1011, vol. 130, p. 435. 
Cull: Ztschr. f. ration. Med., L854, X.I'., vol. I. p. 80. 
<;..itli,'!, ii. Magnus: Arch. E. exp. Path. u. Pharm., 1001, vol. 45. 
Grttner: Jahrb. f. Kinderh., L906, vol. 64. 
Grflnwald: Arch. f. exp. Path. a. Pharm., L909, vol. 00. 
Hadinger n. Takayaseu: Dent. Arch. f. klin. Med.. 1S01. 
Halsey u. Meyer: Marburg. Sitzun^sber., .luli, 1002. 
Hermann: !Sitzungsbcr. d. Wien, Akad., 1850, vol. 30. 
23 



354 PHARMACOLOGY OF RENAL FUNCTION 

Jehle: Die lordotische Albuminurie, Wien, 1909. 

Loewi: Arch. f. exp. Path. u. Pharm., 1902, vol. 48, p. 410. 

Magnus: Arch. f. exp. Path. u. Pharm., 1901, vol. 45. 

Nishi: Arcli. f. exp. Path. u. Pharm., 1910, vol. 62, p. 329. 

v. Noorden's Path. d. Stoffw., 190G, vol. 1, p. 1003. 

Pollak: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 157. 

Richet: Trav., 1893, p. 198. 

Schlayer: Pfliiger's Arch., 1907 (Urannephritis) . 

v. Sobieranski: Arch. f. exp. Path. u. Pharm., 1895, vol. 35. 

Sollmann, T. : Am. J. of Phys., 1902, vol. 8, p. 155, here lit. 

Starling: Journ. of Physiol., 1899, vol. 24, p. 317. 

Tamilian: Ztschr. f. physikal. Chem., 1896, vol. 20. 

Widal et Javal : Compt. rend, de la Soc. Biol., 1903. 

FACTORS CONTROLLING DIURESIS 

These factors mentioned as being of moment for diuresis, — namely, 

Hydraemia, with its influence on "Quellungs" pressure and the 
osmotic tension of the blood ; 

Blood-pressure and rapidity of the blood flow in the renal 
vessels ; 

Reabsorption and secretion in the tubules, may be pharmaco- 
logically influenced at times in common and, in so far as they do not 
depend upon one another, at times separately. 

Alteration of the Water Content of the Blood 

1. Hydraemia necessarily results from drinking liquids or eating 
food containing much water. The water which is drunk dilutes the 
blood to a moderate degree (Buntzen) and is excreted in the urine in 
the course of 6-7 hours (Falck), and, as water containing carbonic acid 
is absorbed more quickly (see p. 173) , it is excreted more rapidly. After 
this has occurred the amount of water in the body remains the same as 
it was previously, for diuresis, thus stimulated, results only in a 
washing out of the body and a dilution of the urine. Such dilution 
of the blood may be beneficial in chronic poisonings and in conditions 
of abnormal metabolism, while increased diuresis may be useful in 
disease of the urinary tract, such as pyelonephritis, cystitis, or uratic 
concretions. 

It is clear that the same indication may be met, in case of need, by 
subcutaneous or intravenous administration of isotonic saline solution. 

If, on the contrary, it is desirable to remove water from the body 
by causing increased diuresis, the necessary hydremia must be" 
obtained at the expense of the water contained in the tissues. A 
transudation of the lymph-plasma into the blood will do this, for 
the lymph contains only about one-third as much proteid as does the 
blood-plasma. This occurs, for example, after extensive blood letting, 
which may therefore have a diuretic effect (Leube, Geelmuyden, 
Laache). 

The Production of Hydremia by the Use of Salts. — The osmotic 
tension of the blood may be increased by the administration of sub- 
stances which penetrate through the cell membranes only slowly or 



HYDREMIA AS CAUSE OF DIURESIS 355 

not at all, thus attracting the water from the tissues into the lymph 
and blood. This is another means which may be employed to produce 
hydremia. It is a self-evident prerequisite for the value of this pro- 
cedure that the substances employed can readily pass through the 
glomerular membranes and thus do not oppose any osmotic resistance 
to filtration at this point. If they then pass into the tubules with 
the water from the blood, they will, by their osmotic pressure, prevent 
the reabsorption of the water, in this way, too, increasing the amount 
of urine. 

"The diuretic salt action," according to this conception, is then 
produced in two fashions, — first by causing hydramiia, and second 
by inducing a "diarrlicea in the tubules." Probably a third factor 
is active here, an "Entquellung" * of the blood-plasma by the salts, 
the blood colloids being thus deprived of some of their water, which 
water is rendered more readily filterable by being freed from the 
"Quellungs" pressure which opposes the filtration (Hoppe-Seyler, 
Runeberg) . Colloids like gum arabic or gelatin (0.6-1.0 gm. per kilo) , 
when injected intravenously, inhibit diuresis, but if sodium chloride 
be subsequently injected, free diuresis occurs as a result of the 
"Entquellung" of the colloids. Moreover, the flow of blood through 
the renal vessels is facilitated by addition of salt to the blood, for the 
renal tissues shrivel up somewhat as a result of losing part of their 
water; thus the lumen of the blood-vessels becomes wider (Sollmann) . 

The diuretic effect of the salts is, other things being equal, inversely 
proportional to their power of diffusion. As a matter of fact, the 
immediate diuretic effect when solutions of the but slightly diffusible 
Na 2 S0 4 or NaIIC0 3 are introduced into the blood is markedly greater 
than occurs after injection of equal amounts of isosmotic solutions 
of NaCl or sodium nitrate, which diffuse much more readily into cell 
membranes (Halsey, Magnus, dishing, Miinzer, and others) . 

In such experiments, as should be expected, the poorly diffusing 
sodium sulphate is excreted in larger amounts and with greater 
rapidity than is the readily diffusible sodium chloride. In other 
words, it is more "harnfahig"f than NaCl, for during the relatively 
long passage through the uriniferous tubules the Na 2 So 4 is absorbed 
to a much slighter extent than is the NaCl. Diuresis caused by Na.,S0 4 , 
therefore, is more intense and passes off more rapidly than that caused 
by NaCl.t 

For practical use, however, only substances relatively easily ab- 
sorbed from the intestines — i.e., of the salts, only the readily diffusible 
ones, especially NaCl and potassium nitrate and acetate — may be 

* By this apparently untranslatable German term is meant the attraction 
to and combination with the Baits of a portion of the water previously firmly 
combined with the colloids of the plasma. 

+ Harnfahig means readily excreted in the kidnej\ 

X [Sodium sulphate has a greater power of attracting the water from its com- 
bination with proteid and consequently causes a greater hydremia. — Ttt.] 



356 PHARMACOLOGY OF RENAL FUNCTION 

administered for this indication.* Of these the acetate after absorption 
is changed in the blood into the less diffusible and, therefore, diureti- 
cally more active carbonate. This would appear to account for the 
preference given it as a diuretic. 

Contraindications. — It is necessary, however, again to emphasize 
the fact that in many cases of disease the administration of sodium 
chloride does not increase but, on the contrary, diminishes the secre- 
tion of urine, even though the blood is rendered more hydremic as 
a result of the attraction of water into it from the tissues, which 
occurs when the sodium chloride in the blood is increased. In such 
cases it would appear that the glomerular membrane has become 
relatively impermeable for NaCl, and that therefore this salt offers 
an osmotic resistance to the excretion of water; here, by administer- 
ing a diet poor in salt, the osmotic partial pressure of this salt may 
be lowered and an increased urinary secretion result (Nils Finsens). 

Urea as a Diuretic. — The same effect may also be obtained at 
times by the administration of substances which act like salts but 
for which the glomerular membrane is still permeable, — for example, 
by the administration of urea, of which 10 gm. are approximately 
isosmotic with 5 gm. NaCl or 8 gm. potassium acetate. According 
to this, it would be necessary to administer at least 20-40 gm. of urea 
daily to produce a pronounced effect (Elemperer) . Urea, while 
passing readily through the intestinal epithelium and permeating 
rapidly into the blood-cells, passes into the muscle-cells and the epi- 
thelial membrane of the urinary tract with great difficulty (Oryns, 
Overton). In the blood and tubules, therefore, it has a strong power 
of attracting water to itself. Such elective semi-permeability is often 
met with in the organism, although it cannot be explained chemically. 

Sugars as Diuretics. — Glucose, and, in a greater degree, the poorly 
diffusing milk-sugar, when taken in amounts of 100-200 gm. dis- 
solved in as little water as possible, are stated to cause diuresis 
and absorption of cedema. When they pass into the blood, they cause, 
presumably by osmotic action, a temporary hydrasmia (Meilach). If 
they pass into the urine, as in diabetes mellitus, they must, like the 
salts, hinder reabsorption in the tubules and produce, as it were, 
a "renal diarrhoea." 

Mercury as a Diuretic. — Finally, hydremia may be induced by 
mercurial preparations, especially by calomel, of which doses of 0.2 
gm., several times daily, produce a marked diuresis, especially if the 
tissues are oedematous and diarrhoea is prevented by opium. 

According to Fleckseder (unpublished experiments), the hydremia 
caused by calomel is induced as follows : The increased secretions and 
the partially prevented reabsorption in the small intestine, together 
with the actively stimulated peristalsis, cause the accumulation in the 

* [M. Fisher believes that the saline cathartics as ordinarily administered are 
absorbed in sufficient amounts to cause a hydremia and thus to cause increased 
diuresis. — Tr.] 



FACTORS INFLUENCING RENAL CIRCULATION 357 

large intestine of large amounts of fluid. If this large quantity of 
fluid is not rapidly expelled from the colon, but remains there for a 
time, it is absorbed by the mucous membrane of the large intestine 
and dilutes the blood, which in the meantime, by attracting water 
from the cedematous tissues to replace that lost to the intestine, has 
already regained its original concentration. The blood which has 
thus been rendered hydremic then gets rid of its extra water through 
the kidneys, and a marked diuresis occurs. 

The diuretic effect of the mercurials appears not to depend at all 
on, nor to be related in any way to, the very harmful action exerted 
on the renal epithelium by its soluble preparations, such as corrosive 
sublimate. 

BIBLIOGRAPHY 

Bauer: Ztsclir. f. Biol., 1872, vol. 8. 

Buntzen: Om Ermiringen, etc., Kopenhagen, 1879. 

Falck: Ztschr. f. Biol., 1872, vol. 8. 

Finsens, Nils: Krankheit, Therap. d. Gegenw., July, 1905. 

Geelmuyden: Dubois' Arch., 1892. 

Gryns: Pfhiger's Arch., 189G, vol. 63. 

Handowsky: Fortschr. in d. Colloidchemie der Eiweisskorper., Dresden, 1911. 

Hoppe-Seyler : Virchow's Arch., 1856, vol. 9, p. 260. 

Klemperer: Berl. klin. Woch., 1896. 

Laache: Die Aniimie, 1897. 

Leube: Pentzold's Hdb., vol. 7, p. 250. 

Lillie, R.: Am. Journ. of Physiol., vol. 20, 1907, No. 1. 

Ludwig: Lehrb., vol. 2, p. 428. 

Magnus: Arch. f. exp. Path. u. Pharm., 1901, vol. 45, pp. 23 and 25. 

Meilach: These de Paris, 1889. 

Overton: Z. f. physikal. Ch., 1897, vol. 22, p. 189. 

Pribram, E.: Colloid-chem. Beihefte, 1910, vol. 2, Nos. 1 and 2. 

Pugliese: Ztschr. f. Biol., 1910, vol. 54. 

Runeberg: Deut. Arch. f. klin. Med., 1884, vol. 35, p. 266. 

Sollmann: Am. Journ. of Physiol., vol. 9, p. 454. 

Strubell: Der Aderlass, Berlin, 1905, lit. here. 

2. The rate of flow and the pressure of the blood in the renal 
vessels depends, on the one hand, on the resistance in them and, on 
the other, on the functional performance of the heart and on the 
general blood-pressure. 

Stasis. — The resistance to the blood flow in the kidney may be 
a hindered outflow from the renal veins, as, for example, in cardiac 
stasis, in which case an improvement of the cardiac function relieves 
the oliguria (see p. 296). The outflow from the renal veins may also 
be hindered by a collection of fluid in the abdominal cavity, and, 
if the fluid be removed by aspiration, the previously halting secretion 
of urine may become normal again. Further, if the amount of fluid 
in the abdomen be diminished by other means, — for example, by the 
removal of large amounts of: water by way of the intestines, as a 
result of the administration of Epsom salts or of drastic cathartics, 
or by excessive sweating, — the pressure on the vena cava is lessened 
and, as a rule, improved diuresis results. In this indirect sense, 
cathartics and sudorific drugs may, under pathological conditions, 



358 PHARMACOLOGY OF RENAL FUNCTION 

increase the secretion of urine, in place of diminishing it as they do 
under normal conditions [see footnote, p. 356. — Tr.]. 

Renal Vasoconstriction. — Resistance to the blood flow through 
the kidney may also be due to a more or less pronounced contraction 
of the renal arteries and capillaries. 

Our knowledge of the variations in the tone of the renal vessels 
is very imperfect. Sensory stimuli, especially those arising in the 
urinary tract, not infrequently cause long-continued reflex anuria, 
which probably is due to a tonic contraction in some portion of the 
renal vascular system, whether in the glomerular vessels or in the 
vasa efferentia or in the capillaries is uncertain. Moreover, in many 
forms of acute nephritis with scanty secretion of urine, it is possible 
that the abnormal contraction of individual groups of the renal vessels 
may be the cause of the oliguria. Finally, it is conceivable that the 
calibre of the uriniferous tubules may change and under some con- 
ditions oppose a high resistance to the passage of urine. The richness 
of the nerve supply in their membrana propria (Disse) speaks for 
the possibility that this may occur. 

Indirectly the amount of blood flowing through the kidney may be roughly 
estimated, and the degree of resistance may be directly determined by the use 
of the oncometer if care be taken to prevent any hindrance to free outflow of 
the venous blood and urine; but this method gives no information about the 
distribution of the blood in the different renal vessels. It is possible, too, that 
dilatation of the vessels and the resulting increased blood flow may occur without 
any increase in the volume of the kidney, this occurring at the cost of other 
compressible parts of the kidney — for example, of the tubules — or as a result 
of an " Entquellung " or shrinking of the capillary epithelium (Sollmann). 
Consequently the rate of the blood flow through the kidney may not under all 
conditions be deduced from the changes in its volume (Loewi). 

The renal vessels may be contracted as a result of reflexes from 
sensory stimuli, especially those resulting from cooling of the skin 
(Wertheimer) . Drugs which, like strychnine, increase the reflex 
tone of the vasomotor centres, may also cause constriction of the 
renal vessels. However, this centrally induced vasoconstriction in 
the kidney is not a lasting one, being much less persistent than the 
constriction of the intestinal vessels, and after a short time the renal 
vessels again dilate. The blood forced from the other still contracted 
vascular systems will then flow so much the more freely through the 
kidney, and an active diuresis results. The effect of the renal vasodi- 
latation following such reflex renal vasoconstriction is evidenced by the 
desire to urinate which is often experienced after, or even during, a 
cold bath. The peripheral action of epinephrin appears to produce 
a similar effect in the kidney. [With pituitrin this effect is still more 
pronounced. — Tr. ] 

RENAL VASODILATATION 

Chemical influences of varying nature may cause dilatation of the 
renal vessels by a direct action on their walls. 

Hydremia of any type causes a dilatation of the renal vessels, 



RENAL VASODILATORS 359 

and therefore all agents causing hydraemia indirectly produce this 
effect. 

It has been found that with the occurrence of hydraamia, no matter 
how occasioned, the volume of the kidney is regularly increased, and 
that the blood flows through it more rapidly and that, too, even after 
the kidney vessels have been isolated from central nervous influences 
by destruction of their nerves. Therefore, it would appear that the 
amount of water in the blood — or, otherwise expressed, the "Quel- 
lungs" pressure of the blood — exerts a direct influence on the tone 
of the renal vessels and in this way regulates the blood flow through 
the kidney in a purposeful manner (Loewi). 

Almost All Substances "Which aee Excreted by the Kidney 
Cause Dilatation of Its Vessels (Abeles, Grutzner). — The kidney 
is the excretory organ for most of those substances which simply pass 
through the body. Just as the intestine, in order rapidly to rid the body 
of many harmful substances, reacts to them with hydraemia of the 
mucous membrane, diminished absorption, increased peristalsis, and, 
in case of more powerful irritation, with free transudation, it would 
appear that almost all the substances foreign to the body which must 
be excreted by the kidney cause active vasodilatation in this organ and 
increased diuresis. Many of these substances also, even in very small 
amounts, cause degenerative changes in the kidney, and thus, in spite 
of their poiverfid primary diuretic effect, are not useful practically 
or are perhaps directly harmful. Cantharidin, formerly much used 
in the treatment of dropsy, acts in this fashion. 

Other substances cause these degenerative changes only when they 
reach the kidney in large quantities or in high concentration, but are 
ordinarily harmless and may be used as mild kidney stimulants. In 
this group belong many, perhaps all, of the so-called ethereal oils, 
which are present in very small amounts in numerous drugs and 
which may well be responsible for the diuretic action attributed to 
many of them. Some of the substances mentioned above as inducing 
hydraemia, especially urea, and perhaps also potassium nitrate, appear 
also to possess a similar direct vasodilating action and the power of 
accelerating the blood flow in the kidneys. 

Those narcotics, such as alcohol, amylene hydrate, paraldehyde, 
etc., which are excreted by the kidneys, may produce similar effects, 
but with them their specific narcotic action, which includes their power 
of lessening reflex actions, may also be of importance, especially in 
cases of reflex anuria (Mori). 

BIBLIOGRAPHY 
Abclea: Wicn. Sitz.-Ber., 1883, vol. 87. 
Disse: Marburgcr Sitzungsboriehto, 1898. 
(Initzner: PflMgor's Arch., 1875, vol. 11. 
Loewi: Arch. f. exp. Patli. u. Pliarm., 1905, vol. 53. 
Mori: Arch. f. Hygiene, 1888, vol. 7, p. 354. 
Sollmann: Am. Jonm. Physiol., 1903, vol. 9, p. 454. 
Wertheimer: Arch, de Physiol., 1893. 



360 



PHARMACOLOGY OF RENAL FUNCTION 



SPECIFIC RENAL VASODILATING DRUGS 
Substances belonging to the purine group, caffeine, theobromine, 

and related substances, dilate the renal vessels in an entirely peculiar 

and elective fashion. 

Caffeine, or theine, trimethylxanthine, occurs in the following 

proportions in various plants : 

In coffee bean, up to 2 per cent.; in tea leaves, up to 4 per cent.; in cola 
nut, up to 2 per cent.; in guarana, up to 5 per cent.; and in Paraguay tea and 
other plants, in still larger proportions (Goris et Fluteaux). In pure state it 
forms shining silky crystals, very soluble in boiling water, but at 15° C. requiring 
80 parts for their solution. In its chemical constitution it closely resembles 
theobromine and its isomer, theophylline, as also xanthine and uric acid, while 
synthetic chemistry has furnished a number of other closely related substances. 
All these substances are substitution products of the purin nucleus. 



N=CH 

I I 
CHC— NH V 

"J— n) CH 



NH— CO 



C— NHs 



N 



NH- 



■L 



Nil 



CO 



Purine 



Uric acid 




NH— CO 
I I /CH 3 

CO C— N< 

I II 

CH 3 N- 



J-N> 



NH— CO 

I I 
CO C— NHv 

I II >CH 

NH— C N^ 

Xanthine 

CHs N— CO 

CO C— NH X 
I II >.CH 

CH 3 N— C- 



■N^ 



Theobromine 



Theophylline 



The diuretic effect of coffee, tea, and caffeine has long been known 
and used in therapeutics (Bouchardat, 1859). For a long time the 
views concerning the manner in which it caused diuresis were very 
contradictory. Some authorities — as, for example, Biegel — as late 
as in 1884 considered this to be an indirect action similar to that of 
digitalis, while others, among them Curschmann in 1885 and Bronner 
in 1886, as a result of their clinical observations, pronounced the 
caffeine diuresis to be independent of any cardiac and vascular action 
and attributed it to a specific stimulation of the kidney. 



CAFFEINE 

It has already been stated that caffeine exerts a marked influence 
on the circulation, but this effect is entirely different from that of 
digitalis, consisting of the following factors : 

1. Stimulation of the vasomotor centres causing constriction of 
the arterioles, and, as a result, at times, an increase in the blood- 
pressure. 

2. An influence on the cardiac function in four different ways: 
(a) Stimulation of the inhibitory vagus centre, causing retardation 
of the pulse, (b) Stimulation of the cardiac accelerating ganglia 
in the periphery, causing acceleration of the pulse ; one or the other 
of these two effects preponderating as conditions or individuals may 



FACTORS CONTROLLING DIURESIS 



361 



differ, (c) An effect on the heart muscle, the relaxing power being 
diminished while the contractile energy is increased; as a result 
usually a diminution of the pulse volume of the heart and a fall in 
blood-pressure, (d) Dilatation of the coronary vessels. 

If the vasoconstriction is the preponderating effect, the blood- 
pressure rises above the normal; but if the vasoconstricting centres 
are less excitable than usual or if they have been paralyzed by pharma- 
cological agents such as alcohol, caffeine, as a rule, lowers the blood- 
pressure. However, in neither case would the actions of caffeine cause 
an increase of the blood flow through the kidney or an increased 
diuresis resulting therefrom, for, in case the blood-pressure is raised 
by caffeine, this is due not to acceleration of the blood flow 
throughout the body but to its retardation, just as is the case with 
strychnine. Therefore, only when the insufficient blood flow through 





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O.Ol caffeine 

Fig. 42. — Effects of caffeine on the blood-pressure and renal secretion 
in the chloralized rabbit (u. Schroder). 



the kidney and the halting diuresis is due to the fact that the heart 
is beating feebly, and therefore insufficiently supplying its coronary 
vessels with blood, can the general circulatory action of caffeine cause 
an increase in the secretory activity of the kidney. 

Direct Action on tiie Kidney. — However, even when the heart 
is entirely healthy and receiving the optimal amount of blood, caffeine 
acts as a diuretic. To v. Schroder belongs the credit of having been 
the first to prove experimentally that caffeine diuresis depends essen- 
tially on a specific action in the kidney, by showing that its diuretic 
effects may actually be diminished and under some conditions entirely 
suppressed by the stimulation of the vasoconstrictor centres by caffeine, 
while, on the other hand, marked diuresis occurs when these centres 
have been depressed by chloral, paraldehyde, and similar drugs, or 
when their influence on the renal vessels has been prevented by section 
of the renal nerves. 



PHARMACOLOGY OF RENAL FUNCTION 



Rabbit 

O, Ob.Vorph. rmo: 



Rost's investigations demonstrated, moreover, that the diuretic 
effect occurs only when considerable amounts of caffeine pass into the 
urine, and that consequently its seat of action lies in the renal paren- 
chyma itself. In dogs, in which diuretic effects are obtained only by 
very large doses of caffeine, only 8 per cent, of the caffeine adminis- 
tered passes into the urine, while in rabbits, which react to relatively 
small doses with marked diuresis, more than 20 per cent, is excreted. 
Although v. Schroder explained the diuresis caused by caffeine 
as due to stimulation of the secretory elements of the kidney to 
greater activity, it has not been possible to prove that such a specific 
stimulation of secretory activity occurs. In fact, its occurrence has 
been rendered improbable by the experiments of Loewi, who found 
that during phloridzin glycosuria caffeine increased the amount of 
urine secreted six- or sevenfold, while there was no increase in the 
amounts of sugar excreted, although the sugar is undoubtedly excreted 
by a specific secretory activity of the kid- 
ney. On the other hand, there are two 
other factors definitely established which 
are sufficient to account for the stimula- 
tion of renal secretions by caffeine. These 
are, in the first place, an increased flow of 
blood in the kidney and, secondly, an in- 
hibition of reabsorption in the uriniferous 
tubules. 

Increased Blood Flow. — Caffeine 
and other related substances under all 
conditions cause a dilatation of certain of 
the renal vessels, so that, as a rule, the 
total volume of the kidney is increased, as 
can be shown by the use of the oncometer. 
However, even when the volume of the kidney does not increase of its 
own accord, or when it is kept at a constant volume by firm encapsula- 
tion, it may be demonstrated that the blood flow through the kidney 
is markedly augmented by caffeine, for the blood in the renal veins 
which was previously dark in color now has the color of arterial blood 
{Loewi, Fletcher, Henderson u. Loewi). This effect is independent 
of the renal nerves, for it occurs even many weeks after their division 
and must therefore be due to an action on the muscles in the walls of 
the renal vessels. By such an actively augmented blood flow through 
the kidney the necessary conditions for increased diuresis are estab- 
lished. In accordance with this, it has been found that caffeine 
produces no effect on diuresis if the chief blood paths — that is, the 
vessels of the glomerular loops — are diseased and incapable of react- 
ing, and that caffeine diuresis may still occur if the pathological 
changes have affected essentially only the tubular epithelium 
(Schlayer). 



y\ 












r 


\ 






Sv^ 




























—i- 







0.04 Caffeine 

Fig. 43. — Effects of caffeine on 
the secretion of the normal right and 
the nerveless left kidney. 



CAFFEINE GROUP 363 

The second factor, the inhibited reabsorption, has not been abso- 
lutely proven, but has been shown to be extremely probable. 

Inhibition of Reabsorption. — Evidence of this reabsorption was long 
ago furnished by the staining experiments of Sobieranski, who found that under 
the influence of caffeine the epithelium of the convoluted tubules lost the power 
of imbibing and staining with indigo-carmine, which after injection into the 
blood is excreted in large amounts in the urine and which under normal conditions 
is absorbed by these cells and stains them deeply. 

These experiments indicated, in the first place, that this stain, although 
excreted in the urine, did not pass into it through the tubular epithelium, and, 
in the second place, that when caffeine had been administered this stain could 
no longer pass with the reabsorbed fluid into the epithelial cells as it does nor- 
mally. Otherwise the nuclei would be intensely stained after caffeine just as is 
the case under normal conditions. It, therefore, would appear that caffeine 
inhibits reabsorption by lessening the power of the tubular epithelium to reabsorb 
substances from the glomerular filtrate. 

Further support for this view is furnished by the experiments of Eirokawa, 
who found the osmotic pressure in the renal cortex very constant but varying 
within wide limits in the medulla, and that, in exact proportion to the concen- 
tration of the urine last secreted, it was many times higher here than in the 
cortex. Under the influence of caffeine, however, the molecular concentration in 
the medulla sinks nearly to the level of that in the cortex. This is to be ex- 
plained most simply by the assumption that the cortical secretion or nitrate 
remains unconcentrated, which is equivalent to saying that the normal concen- 
trating reabsorption of the urinary water fails to take place in the medullary 
portion. The observations of GaJeotti and Santa, that only the cortical portion 
and not the straight tubules hypertrophy when compensatory hypertrophy of 
one kidney occurs, would indicate that the medullary portion — that is to say, 
the straight tubules — have no important secretory function. (For lit. see 
Kapsammer. ) 

Grunwald'8 observations on the excretion of the chlorides also point in the 
same direction. He found that rabbits poor in chlorides, which secrete urine 
containing no chlorides, may, by the administration of theobromine, be made to 
excrete them in the urine in such large amounts that they may die because of 
the loss of chlorides. Moreover, the chloride content of the renal cortex, the place 
where the chlorides are excreted, was found to be very constant and almost the 
same in animals whether they were rich or poor in chlorides, while the chloride 
content of the cortex was found to vary parallel with the chloride content of the 
urine and to be regularly increased when theobromine is administered. It appears 
that this is most probably due to the fact that theobromine causes a diminished 
reabsorption of the chlorides in the medullary portion of the kidney. 

Other Actions of Caffeine. — Besides acting on the circulation 
and on the renal function, caffeine increases the general reflex excita- 
bility of the central nervous system and augments the functional 
capacity of the striated muscles. (See appropriate sections.) The 
increased reflex excitability may be observed in both cold- and warm- 
blooded animals after very moderate doses, while in severe poisoning 
in animals it may cause a reflex tetanus. In man the lesser degrees 
of this action express themselves by excitement, sleeplessness, marked 
palpitation, and sometimes also by diarrhoea and vomiting (Kiirsch- 
mann). 

As a Diuretic. — Caffeine, in doses of 0.1-0.3 gin. several times 
daily (0.5 gm. maximal single dose and 1.5 gm. maximal dose for 
24 hours), or the readily soluble double salt caffeine and sodium sali- 
cylate, may cause very marked diuretic effects, provided that the 



364 PHARMACOLOGY OF RENAL FUNCTION 

tissues 'or the body cavities contain sufficient fluid as in cases of cedema 
or exudation [provided also that the kidney is not so damaged that it 
cannot react efficiently. — Tr.]. 

In individuals with readily excitable vasomotor centres the diuretic 
effects of caffeine may be expected to be uncertain, for it stimulates 
these centres in a fashion analogous to, but much more weakly than, 
strychnine, and this central action may counteract the local vasodilat- 
ing action in the renal arteries. In such cases combination with 
alcohol or similarly acting drugs may aid in producing the desired 
effect. 

The diuretic action of theobromine and theophylline, which are 
chemically so closely related to caffeine, is even more reliable than 
that of caffeine, for they cause hardly any central stimulation. 

Theobromine is very insoluble in water, and is therefore advan- 
tageously administered in the soluble but very alkaline double salt 
theobromine and sodium salicylate, diuretin, in doses of 0.5-1.0 gm. 
(6.0 gm. per diem), or as theobromine and sodium acetate, known as 
agurin, in like dosage. Disturbances of the stomach and intestines are 
more readily caused by these drugs, however, than by caffeine. 

Theophylline, or theocin, is stated to be an even more powerful 
diuretic, especially in doses of from 0.2-0.5 gm., but it readily causes 
disturbances of the stomach, vomiting and diarrhoea, and in doses of 
1.0 gm. per diem has occasionally caused violent epileptic attacks in 
epileptic patients (Schlesinger) . Not more than 0.8 gm. of the pure 
theophylline or 1.5 gm. of its sodium acetate should be administered 
daily. 

As theobromine and theophylline also exert the same peculiar action on the 
striated muscles as caffeine, one might be tempted to believe that the muscle action 
and the diuretic action are in some way due to a common cause. The parallelism 
of these two actions is, however, only an accidental one, and is not observed in a 
whole series of other synthetically prepared purine derivatives. Thus, acetyl- 
amidocaffeine, diacetylamidocaffeine, and caffeine methylendiamin hydrochlorate 
possess no action on the muscles and are in other respects practically without 
toxic action, while they exert the specific diuretic action in a high degree 
(H. Meyer, unpublished experiments). 

In conclusion one more important point should be emphasized. 
While all so-called irritant diuretics, spices, ethereal oils, cantharides, 
metallic salts, and even concentrated salt solutions, when administered 
subcutaneously damage the kidney and cause albuminuria, the drugs 
of the caffeine group cause no pathological alterations in the kidney, 
even when they are administered repeatedly in large or even in poison- 
ous doses. They may, therefore, be administered during long periods, 
and even in the presence of parenchymatous nephritis, with less risk 
than any other diuretics. It is even possible that the improved blood 
flow to the kidney may exert a beneficial effect on the diseased organ 
(Loewi). 



DIGITALIS AS A DIURETIC 365 

BIBLIOGRAPHY 
Albanese: Arch. f. exp. Path. u. Pharm., 1894, vol. 34. 
Bondzynski u. Gottlieb: Arch. f. exp. Path. u. Pharm., 1896, vol. 36. 
Fletcher, Henderson u. Loewi: Arch. f. exp. Path. u. Pharm., 1905, vol. 53. 
Galeotti u. Santa: Ziegler's Beitrage, 1902, vol. 31. 
Goris u. Fluteaux: Bull, science Pharm., 1910, vol. 17, p. 599. 
Griinwald: Arch. f. exp. Path. u. Pharm., 1909, vol. 60. 
Hirokawa: Hofmeister's Beitrage, 1908, vol. 11. 

Kapsammer: Nierendiagnostik u. Nierenckirurgie, 1907, vol. 2, p. 560 ff. literat. 
Koschlako: Virchow's Arch., 1864, vol. 31. 
Kurschmann: Deut. Ivlinik, 1893. 
Loewi : Arch. f. exp. Path. u. Pharm., 1902, vol. 48. 
Loewi : Marburger Sitz.-Ber., 1904. 
Loewi: Wien. klin. '\Yoeh. J 1907, No. 1. 
Mever, H: Marb. Sitz.-Ber.. 1902. 

Eost: Arch. f. exp. Path. u. Pharm., 1896, vol. 36, p. 18. 
Schlayer: Verh. d. Kongr. f. inn. Med., 1906. 
Schlesinger: Miinch. med. Woch., 1905, No. 23. 
v. Schroder: Arch. f. exp. Path. u. Pharm., 1887, vol. 22, p. 39. 
Sobieranski: Arch. f. exp. Path. u. Pharm., 1895, vol. 35. 

EFFECTS OF THE DIGITALIS SUBSTANCES ON THE PENAL 
BLOOD FLOW 

The members of the digitalis group resemble the purine bodies in 
one particular, — that is, in their power actively to dilate the renal 
vessels. 

While it is well known that the most important therapeutic prop- 
erty of this group is their power of improving a pathologically weak- 
ened heart function and in this way increasing diuresis indirectly by 
improving the general circulation, it was emphasized by Lauder- 
Brunton and Power, as early as 1874, that digitalis may act as a 
diuretic even in normal men in whom the heart function is an optimal 
one. It may also be shown, as has recently been done by Loewi and 
Jonescu, that increased diuresis occurs in the normal healthy animal 
after digitalis and especially after doses so small as to cause no rise 
in the blood-pressure. Under these conditions the oncometer shows 
that there is a marked increase in the volume of the kidney, indicating 
dilatation of the vessels and increased flow of blood through it. In 
accordance with this is the fact, long known by clinicians, that digitalis 
increases the diuresis in cardiac patients and causes a disappearance 
of cedema, usually without increasing the blood-pressure, and often 
in fact when the pulse is markedly slowed and the pressure in the 
large arteries decidedly diminished. 

This action of digitalis on the renal vessels is a purely local one, 
for it also occurs in a kidney which has been deprived of its nerves. 
In this particular <li.uitalis acts in the same way as caffeine and its 
congeners. As, however, digitalis does not appear to exert the second 
diiir< sis-producing action of caffeine, the inhibition of reabsorption, 
its direct diuretic effect is only slight as compared with that of 
caffeine. 

BIBLIOGRAPHY 
Lauder-Bruntou and Power: Zentralbl. f. hum]. Wiss., 1874. 
Loewi u. Jonescu: Arch. f. exp. Path. u. Pharm., 1908, vol. 59. 



366 PHARMACOLOGY OF RENAL FUNCTION 

3. SECRETION AND REABSORPTION IN THE TUBULES 

"Whether or not it is possible by the use of pharmacological agents 
to cause or to increase the excretion of water by the tubular epithelium 
is not known with certainty (Frey). 

The limitation of the reabsorption of water in the tubules, which 
may be considered as analogous to diarrhoea in the intestines, has been 
shown to be one of the factors in the action of the diuretic salts as 
well as that of caffeine. As an unmixed diuretic action it occurs in 
phloridzin diabetes. 

Phloridzin Diuresis. — Phloridzin is a glucoside but slightly 
soluble in cold water, readily soluble in alkalies and in alcohol, that 
occurs in the roots of apple, cherry, and plum trees, v. Mering dis- 
covered that internal administration and, even better, the subcu- 
taneous injection of small amounts of phloridzin, caused a pro- 
nounced glycosuria, which, as has been shown by later experiments, 
is due to the formation and excretion of glucose in the kidney. The 
sugar after being excreted into the tubules hinders the reabsorption 
of water by its osmotic power, — that is to say, by its power of attract- 
ing and holding water (Loewi, Loewi u. Neubauer). 

If the kidney be diseased, the glycosuria occurs more tardily and 
weakly or not at all. This has led to an attempt to use the glycosuria 
reaction to this drug for the functional diagnosis of the kidney (Kap- 
sammcr). The dose administered hypodermically in such cases is 
0.01 gm. in alkaline or dilute alcoholic solution. 

In diabetes insipidus the indication is to limit the excretion of 
urine, some cases excreting very large quantities (up to 10 1. or more) 
of very dilute urine, which causes a constant thirst and forces the 
patient to consume correspondingly large quantities of water. The 
cause of this disease in many cases is a disturbance in the central 
nervous system, presumably a chronic excitation of the vasodilator 
nerves. In accordance with such assumption, large doses of narcotics, 
opiates, valerian, etc., at times favorably influence the condition, at 
least temporarily. [Strychnine is also apparently at times of value in 
the treatment of this condition. It is possible that the good results 
following its administration may be due to a centrally excited constric- 
tion of the renal vessels. — Tr.] 

BIBLIOGRAPHY 
Frey: Pfiiiger's Arch., 1906, vol. 112. 
Kapsammer: Nierendiagnostik, 1907, p. 87, here lit. 
Loewi: Arch. f. exp. Path. u. Pharm., 1903, vol. 50. 
Loewi u. Neubauer: Arch. f. exp. Path. u. Pharm., 1908, vol. 59. 
v. Mering: Verh. d. Kongr. f. inn. Med., 188G. 

INFLUENCE OF GENERAL AND RENAL METABOLISM ON THE COM- 
POSITION OF THE URINE 

It is evident that the chemical composition of the urine will 
depend on the metabolic processes, on the diet, and also on foreign 



URINARY ANTISEPTICS 367 

substances, taken intentionally or otherwise, which, are excreted in 
the urine in altered or unaltered form or combination. Ever since 
the investigations of Schmie'deberg dealing with the formation .of 
hippuric acid in the kidney, it has been known that the kidney itself 
is capable of both synthetic and catabolic activity and in such fashion 
plays a role in determining the composition of the urine. 

URINARY ANTISEPTICS 

The power which the renal parenchyma possesses of splitting up 
substances into simpler components is possibly of much significance 
for the action of some of the urinary antiseptics. These are sub- 
stances which, when introduced into the body, become active chiefly 
or only after being split up in the kidney. In this group belong, 
among others, uva ursi, which is used as an infusion or fluid extract 
in the treatment of cystitis. It contains, in addition to some tannin, 
the glucoside arbutin, which is split up in the kidney into sugar and 
the antiseptic hydrochinone (see p. 514) . Salol, much used as a urinary 
antiseptic, may possibly owe its activity to a similar decomposition, 
and possibly the same is true of the ethereal oils of copaiba, sandal- 
wood, and cubebs. In the metabolism these are combined with acids, 
with the formation of the inactive ethereal sulphates and glycuronates, 
which possibly are again changed into the active form by decompo- 
sition taking place in the kidney. According to Jordan, the oil of 
sandal-wood exerts a powerful effect, particularly in staphylococcus 
infections. 

Formaldehyde Derivatives. — However, all the urinary antiseptics 
thus far mentioned are far less effective than hexamethylenamine 
(urotropine) and some closely related substances, such as helmatose 
or new urotropine, which is hydromethylencitrate of urotropine, and 
hippol, which is methylenhippuric acid, and others. The activity of 
these substances depends on the fact that formaldehyde is split off 
from them (Jordan). 

Hexamethylenamine. — The decomposition of hexamethylenamine 
occurs but slowly under the influence of a neutral reaction, much more 
rapidly in an acid medium, and not at all in an alkaline one. Its effi- 
ciency is therefore lessened by the simultaneous administration of alka- 
lies, ;md favored when acids, such as acid phosphates, are administered. 
The urine in cystitis, as a rule, does not become alkaline until it is de- 
composed by bacteria in the bladder, and is usually acid when it leaves 
the kidney, so that there formaldehyde can be formed from the hexa- 
me1 liylenamine. Hippol, on the other hand, is more readily decom- 
posed in the presence of an alkaline reaction. These preparations, 
hexamethylenamine or hippol, in a dosage of 0.5-1.0 gm., 4-6 i. d., will 
prevent with reasonable certainty, ammoniacal fermentation and the 
formation of phosphatic concretions occasioned by it. Other urinary 



368 PHARMACOLOGY OF RENAL FUNCTION 

infections are affected by them in varying degree according to the 
resistance of the infecting organisms. The typhoid bacilli seem to be 
more readily overcome than any others (R. Stern), 

BIBLIOGRAPHY 

Jordan, A.: The Action of Urinary Antisept., Biochem. Journ., 1910, vol. 5, p. 274, 

here« literature. 
Stern, R.: Z. f. Hygiene u. Infektionskr., 1908, vol. 59, p. 129. 

Alkalization of Urine. — Acid urine may be readily rendered 
alkaline by the administration of alkaline salts or the salts of the 
vegetable acids, or simply by a diet consisting chiefly of vegetables 
and fruits. By such measures it is possible to cause an excretion of 
the alkaline carbonates in the urine "which will neutralize the acids 
normally present. Such measures, as a rule, increase the ion concen- 
tration of the urine. In case it is wished that the urine be rendered 
alkaline without at the same time becoming more concentrated, such 
alkalies as magnesia, calcium carbonate, etc., should be administered. 
These are not absorbed, but neutralize the acids in the intestine and 
deprive the urine of a portion of its acid constituents. Such effects 
appear to be of value when the indication is to bring about the solu- 
tion of uratic concretions in the kidney and bladder. The recognized 
value of the waters containing the alkaline earths in the treatment of 
the uric acid diathesis depends on such action. 

Atophan. — The excretion of uric acid by the kidney is not appre- 
ciably affected by alkalies, but phenylchinolincarbonic acid, C 16 H 11 N0 2 , 
atophan, in doses of 2 to 3 gm. daily, very markedly increases the 
excretion of this substance in a way which is not yet understood. As 
a result of the increased removal of the urates from the blood, the 
deposits of the urates in the joints and elsewhere pass into solution, 
and the symptoms due to them are relieved. ( Weintraud, also consult 
p. 421.) 

BIBLIOGRAPHY 
Weintraud: Tlier. d. Gegenw., 1911, p. 97. 



CHAPTER XI 

PHARMACOLOGY OF THE SECRETION OF SWEAT 
PHYSIOLOGY 

Composition. — The sweat, containing from 97.5 to 99.5 per cent, 
of water, contains less solid matter than any other secretion of the 
body (Harnack) . Excluding foreign admixtures from the sebaceous 
glands, almost three-quarters of its solids, which amount to 0.5-2.5 
per cent., are inorganic salts, chiefly NaCl, only traces of phosphates 
and sulphates being present (East). Urea makes up more than one- 
half of the organic constituents, which otherwise consist of urates, 
creatin, aromatic acids, ethereal sulphates, and other nitrogenous 
metabolic products which are excreted in the sweat. 

Under aA T erage conditions of intake and output of water, amount- 
ing to about 3 litres per diem, the loss by sweating amounts to about 
40 c.c. per kilo of body weight every hour, which for 24 hours amounts 
to about 700 c.c. for an average weight of 70 kilos (Schwenkenbecher) . 
These figures hold, however, only during rest and with moderate exter- 
nal temperatures, for under other by no means unusual conditions 
the loss of water through the skin may be greatly increased. 

Cramer estimates, from the amounts of sodium chloride on the surface of 
the skin, 814 c.c. during exercise out of doors, and 320S c.c. for 24 hours during 
marching in summer heat. Sweat baths and similar procedures cause much 
more rapid sweat secretion, for example, %-l litre in a half hour (Strauss), 
but this naturally only for comparatively short periods. The enormous number 
of the sweat-glands in some situations, 500-1900 to each square centimetre of 
skin, explains their great efficiency. 

As the estimation of the NaCl on the surface of the skin has shown that 
sweat secretion in man continues under all external conditions of temperature 
(Cramer), although only in almost imperceptible amounts during cold weather, 
it is improbable that water vapor passes through the epidermis as a result of 
purely physical processes and without the aid of the sweat-glands (Schwenken- 
I,, cJu r I . 

Excretion of Nitrogen and Salts. — In spite of their low concen- 
tration in the sweat, the absolute amounts of urea and salts thus 
lust by the body are not to be disregarded, even under normal con- 
ditions, Cramer finding 3.7 gm. NaCl and up to 1.0 gm. N excreted 
by the skin in 24 hours under conditions of moderate exercise in the 
Bummer, while during hard work in high temperatures the sweat 
secreted may contain as much as 12 per cent, of the total N excreted. 
With patients at rest and with mean external temperatures 0.3 gm. 
NaCl and about the same amount of nitrogen represent average fig- 
ures, which are increased by thorough sweating up to 1.0 gm. of each 
in 24 hours (Schwcnk< nln flier u. Spctta). The concentration of 
sweat is increased during active perspiration, but when this becomes 
24 369 



370 PHARMACOLOGY OF SECRETION OF SWEAT 

really profuse the concentration falls below normal. Still, with 
impaired renal secretion (anuria in cholera, urasmia, etc.) salts and 
urea may be excreted in the sweat in such quantities that crystals of 
NaCl or clusters of urea crystals have actually been found on the skin. 

Human sweat is usually acid in its reaction, the acidity being probably due 
entirely to the fatty acids from the sebaceous glands, but when sweating is arti- 
ficially stimulated it quickly becomes alkaline like that of the lower animals 
( Tr it mpy, Ca merer) . 

The sweat-glands therefore are to be considered as excretory organs 
for water and salts and also for nitrogenous- metabolic products. 
Under normal conditions, however, their chief function is that of 
regulating the body temperature, by providing for the excretion and 
evaporation of water on its surface (see Pharmacology of Heat Regu- 
lation). 

These glands are very differently developed in different animals and also 
in different parts of the body. In man the whole skin perspires, certain portions 
of the face, the palms of the hand, and the soles of the feet being especially 
richly supplied with sweat-glands ; but in cats and dogs visible perspiration occurs 
only in the hairless soles of the feet, although sweat-glands do exist in other 
portions of the skin. Rats, mice, and rabbits do not sweat at all, while it is 
well known that horses sweat over the entire skin. 

The secretion of sweat is a. true glandular activity, — that is, it, 
unlike that of urine, results from excitation of secretory nerves and is 
relatively independent of the blood-pressure and blood flow, active 
sweating occurring often in conditions in which the skin is very poorly 
supplied with blood (cold sweat, death sweat, etc.), although, gener- 
ally speaking, the secretion is freer when the blood supply is ample. 

Luchsinger, by showing that stimulation of the sciatic excited free sweat 
secretion after ligature of an artery or constriction of a limb, or even 20 minutes 
after amputation, clearly demonstrated that this secretion is independent of the 
blood supply (Kendall, M. Levy). 

Innervation. — The secretory nerves of the sweat-glands belong ex- 
clusively to the sympathetic nervous system (Langley). 

Those for the hind legs of the cat leave the cord partly with the 
twelfth and thirteenth dorsal, but chiefly with the first and second 
lumbar nerves, while those for the forelegs pass out with the fourth 
to ninth dorsal nerves. They all pass through the sympathetic trunk 
and via the sciatic nerve and the brachial plexuses respectively to the 
balls of the feet. The spinal centres consequently no longer control 
sweat secretion in the hind legs after section of the sciatic or of the 
sympathetic trunk above the sixth lumbar ganglion. 

The spinal sweat centres are primarily under the control of the 
thermoregulatory centres in the midbrain, but may also be influenced 
by other parts of the central nervous system, and may be stimulated 
by most various sensory stimuli, which often produce sweating only in 



PHYSIOLOGY 371 

certain limited portions, as, for example, the localized sweating above 
constantly active muscles. The sweating' during nausea and that due 
to stimulation of the cerebral cortex from anxiety or fear are well- 
known examples of the effect of the stimulation of the sweat centres 
associated with stimulation of higher portions of the central nervous 
system (Winkler). 

Heat is the most important physiological stimulus for this excre- 
tion, it exciting these centres through the mediation of higher centres 
which control the regulation of the body temperature (see this chap- 
ter) and send impulses down to them. Kahn has shown that warming 
the blood flowing to the head without warming the rest of the body 
brings about a dilatation of the cutaneous vessels and strongly excites 
the secretion of sweat, thus demonstrating that the mechanism for 
loss of heat by sweating is started working by the action of the higher 
centres on centres in the cord. 

Sweating is excited both by interference with heat loss and by 
increase of heat production — for example, by active muscular exer- 
tion — and also by external heat. In the usually employed sweating 
procedures the attempt is made both to prevent heat loss, by such 
measures as warm covering and packs, and to introduce heat from 
without, as by drinking hot fluids, such as tea or other warm drinks. 

Sweating is also favored by heat applied locally to the secretory 
nerve-endings, for these respond to stimulation more actively if the 
skin be warm than when it is cold (Schierbeck) • in fact, cooling of 
an extremity can entirely prevent any response to stimulation (Ken- 
dall, Langley). 

BIBLIOGRAPHY 

C'amerer: Ztschr. f. Biol., 1900, vol. 41. 

Cramer: Arch. f. Hyg., 1890, vol. 10. 

Harnack: Fortschr. d. Med., 1903, vol. 11. 

Kahn: Engelmann's Arch., 1904, Suppl., p. 130. 

Kast: Ztschr. f. physiol. Chemie, 1887, vol. 11. 

Kendall u. Luchsingcr: Pflliger's Arch., 187G, vol. 13. 

Langley: Journ. of Physiol., 1891, vol. 12, p. 347. 

Langley: Journ. of Physiol., 1895, vol. 17. p. 290. 

Levy: Ztschr. f. klin. Med., 1892 ,vol. 21. 

Schierbeck: Dubois' Arch., 1893, p. 116. 

Schwenkenbecher: Arch. f. klin. Med., 1903, vol. 79. 

Bchwenkenbecher : Verh. d. Kongr. f. inn. Med., 1908. 

Schwenkenbecher u. Spitta: Arch. f. exp. Path. u. Pharm., 1907, vol. 51. 

Strauss: Deut. med. Woch., 1904, No. 30. 

Triimpv u. Luchsinger: Pfltiger'S'Arch., 1878. vol. 18. 

Winkler: Pfluger's Arch., 1908, vol. 125, p. 584. 

DIAPHORETIC DRUGS 

If in fever the cutaneous vessels are contracted, the attempt is 
often made to overcome this by alcohol, which is administered in the 
form of hot diluted alcoholic drinks, with the object of dilating the 
cutaneous vessels in order that an ample blood flow in the skin may 
favor a free perspiration. 



372 PHARMACOLOGY OF SECRETION OF SWEAT 

DRUGS ACTING CENTRALLY 
The secretion of sweat may also be excited by drugs acting on the 
sweat centres as well as by those acting in the periphery. As any- 
thing which stimulates the spinal centres also stimulates the sweat 
centres, strychnine, camphor, picrotoxine, and ammonium salts excite 
sweat secretion in cats, but this effect is not produced after division 
of the sciatics (Luchsinger, Marme, Nawrotzi). Camphor and the 
liquor ammonii acetatis were formerly much used as sudorifics. 

BIBLIOGRAPHY 

Luchsinger: Pfliiger's Arch., 1876, vol. 17, p. 3G9. 
Luchsinger: Pfliiger's Arch., 1878, vol. 10, p. 510. 
Marme: Nachr. d. Gott. Ges. d. Wiss., 1S78. 
Nawrotzki: Zbl. f. med. Wiss., 1878, 1879. 

DRUGS ACTING ON THE PERIPHERY 
The sympathetic nerve-endings in the glands are acted upon by a 
number of drugs which elsewhere act only on autonomic nerve-endings, 
while epinephrin, which elsewhere acts specifically on the sympathetic 
system, has no effect on the sweat-glands, in contradistinction to its 
effect on the glands in the skin of the frog. On the other hand, mus- 
carine, pilocarpine, and physostigmine all excite, while atropine sup- 
presses, the secretion of sweat. Although the innervation of the 
sweat-gland is, as far as is known, purely sympathetic, in their phar- 
macological reactions, their insusceptibility to epinephrin and their 
susceptibility to the autonomic drugs, they behave entirely like organs 
with autonomic innervation. No explanation has thus far been found 
for this striking exception to otherwise apparently general laws. 

Luchsinger long ago demonstrated that muscarine, pilocarpine, physostig- 
mine, and atropine act peripherally in the sweat-glands. Pilocarpine especially 
has a strong sudorific effect in the cat's paw, even after section of the sciatic; 
in fact, at first it acts more strongly on the side where the nerve has been cut 
than on the other side, and the same is true of muscarine (Triimpy), but, accord- 
ing to Luchsinger, the intravenous injection of physostigmine produces no effects 
on the sweat-glands after they have been cut off from their nervous centres. 
Under these conditions it excites secretion only when injected under the skin of 
the paw. These observations are in no way surprising in view of the pharmaco- 
logical characteristics of this drug (see p. 148), for, while everywhere markedly 
increasing the excitability of nerve-endings, it, in contradistinction to muscarine 
and pilocarpine, does not itself act as a direct stimulus. 

It is entirely in agreement with the fact that these drugs act 
peripherally that after an injection of pilocarpine the general sweat- 
ing is preceded by a strictly localized perspiration (Cloetta), which 
after very small doses may be all that occurs (Strauss), and that, on 
the other hand, small doses of atropine given hypodermically may 
produce only a local suppression of perspiration. 

Arecoline, the alkaloid of the areca nut, and nigelline, from the seeds of 
Nigella sativa (Pcllacani), act like pilocarpine, but are of no practical signifi- 
cance. 



DIAPHORETIC DRUGS 373 

In the sweat-glands, as in the salivary glands, pilocarpine and 
atropine are reciprocally antagonistic; but the affinity between atro- 
pine and the nerve-endings is so much the stronger, that pilocarpine 
can start up the sweat secretions again only in case the dose of 
atropine has not been too large, while atropine is able to counteract 
even the strongest pilocarpine action (Luchsinger) . 

The action of nicotine on the secretory nerves of the sweat-glands accords 
fully with other experiences bearing on the action of this drug on the relay 
stations (ganglia) in the vegetative nervous system. Luchsinger found that 
after section of the sciatic it was either not at all or only very slightly active. 
According to Langley, the ganglia of the sudoriparous fibres lie in the sympathetic 
trunk, which arrangement accords with the fact that the primarily exciting 
action of nicotine is localized at this point. 

Central Actions of These Drugs. — Pilocarpine, physostigmine, and nicotine 
also stimulate the spinal sweat centres, as shown by Luchsinger, who found these 
drugs, when injected into the back, produced sweating in the extremities even 
after the arteries supplying them had been ligated. This central action of these 
drugs is to be considered as analogous to that of other central excitants, such as 
camphor, picrotoxin, and many others, for all three at first cause an excitation 
of the cord, which manifests itself by dyspnoea and after toxic doses by convul- 
sions, and which after pilocarpine is especially lasting but with nicotine soon 
passes over into paralysis (Harnack u. H. Meyer). It is readily comprehensible 
that augmentation of the impulses from the centres will be especially effective 
in combination with the simultaneous excitation of the terminal nervous organs. 
This is especially so with physostigmine, whose peripheral action is solely to 
increase the excitability of the terminal nervous organs. 

In therapeutics of the substances mentioned only pilocarpine is of 
importance as a diaphoretic or hiclrotic, while atropine is the most 
important antihidrotic. 

Pilocarpine is derived from the jaborandi leaves obtained from 
different pilocarpus plants, and is accompanied in the leaves of 
Pilocarpus jaborandi by a second alkaloid with similar but very much 
Aveaker actions (Harnack) . The leaves were introduced from Brazil 
in the seventies, but they have been found to be unreliable and uncer- 
tain in their actions, perhaps on account of the presence in them of 
jaborin, a decomposition product of pilocarpine of basic nature and 
atropine-like action, which may also be present in impure pilocarpine. 
The use of the leaves has therefore been abandoned, and properly so. 

The hydrochlorate of pilocarpine is the preparation to be used, 
and it is usually administered hypodermically in doses of 0.005-0.01 
gm. (maximum, for single dose 0.02 gm. ( ! ! Tr.) , per diem 0.04 gm.) 

Usually ten or fifteen minutes after an injection the skin becomes 
reddened and very profuse sweating occurs, lasting about two hours, 
during which time as much as 2 kilos of fluid may be secreted. An 
increase of salivary secretion almost always accompanies or precedes 
tin; sweating and persists somewhat longer. The salivary secretion 
usually is not increased to a disturbing extent, but occasionally the 
effect on the salivary glands exceeds that on the sweat-glands or it 
alone may occur. The secretions of all other true glands are also 
increased, anions I Ik m those of the lachrymal, bronchial, and tracheal 



374 PHARMACOLOGY OF SECRETION OF SWEAT 

glands. The effect on the bronchial glands is of practical importance, 
inasmuch as it may increase the danger of oedema of the lungs in 
individuals already predisposed thereto. This drug produces no de- 
monstrable effects on the renal or lacteal secretions. 

Other Actions. — While an increase in the various secretions may 
be induced by muscarine or nicotine only simultaneously with other 
dangerous symptoms, after pilocarpine this is usually the first effect 
produced, and occurs after such small doses that there is no danger 
to be apprehended from its actions on the various autonomic nerve- 
endings. In its actions on these it closely resembles muscarine and 
nicotine. Its effects on the eye (p. 153) , on the intestine (p. 190) , and on 
the uterus (p. 222) are analogous to those of muscarine, while its action 
on the heart is identical with that of nicotine. These side actions are 
often disagreeable and disturbing when pilocarpine is administered 
medicinally. Especially visual disturbances and nausea and vomiting 
may result from its administration, but colic and diarrhoea occur 
only rarely. As even therapeutic doses excite uterine contractions, 
this drug should not be administered to pregnant women [except 
in the presence of the clearest indications. — Tr.]. 

At the start pilocarpine produces excitation of the central nervous 
system. In animal experiments the paralysis of the vasomotor and 
respiratory centres results only from much larger doses than those 
which cause an increased secretion of sweat. Still the collapse which 
not infrequently has been observed in man, when larger doses of pilo- 
carpine have been given, may be a result of this central paralysis. 
It is therefore contraindicated to use pilocarpine in doses larger 
than 0.01 gm. ! 

According to Eichelberg, pilocarpine causes an increase in metabolism during 
the active glandular activity caused by it. In the fasting animal the increase 
of the CO, excretion during the period of secretion amounts to only about 
9 per cent. (Frank u. Yoit). It is therefore, not very marked, but may well be 
of some importance in causing the wasting which may occur when sweating 
cures are employed (Schwenkenbecher u. Inagaki) . 

Other Diaphoretics. — In addition to pilocarpine, only the sali- 
cylates and other antipyretics are of much importance as diaphoretics. 
These produce their diaphoretic action by their effect on the regu- 
lation of the body temperature, by acting on those higher centres 
which control the spinal sweat centres (see p. 370). 

BIBLIOGRAPHY 

Cloetta, cited by Luchsinger: Pniiger's Arch., 1876, vol. 15. 

Eichelberg: Inaug.-Diss., Marburg, 1903. 

Frank u. Voit: Ztschr. f. Biol., 1903, vol. 44, p. 111. 

Harnack: Arch. f. exp. Path. u. Pharm., 1886, vol. 20, p. 439. 

Harnack u. Hans Meyer: Arch. f. exp. Path. u. Pharm., 1880, vol. 12, p. 296. 

Langley: Journ. of Physiol., 1891, vol. 12, p. 347. 

Langley: Journ. of Physiol., 1895, vol. 17, p. 296. 

Luqhsinger: Pflttger's Arch., 1876, 1877, 1878. 

Marshall: Journ! of Physiol., 1904, vol. 31, p. 120. 



DIAPHORETIC DRUGS 375 

Pellacani: Arch. f. exp. Path. u. Pharm., 1S83, vol. 16, p. 440. 
Schwenkenbecher u. Inagaki: Arch. f. exp. Path. u. Pharm., 1905, vol. 55. 
Strauss: Compt. rend., Paris, 1879. 
Trumpy u. Luchsinger: Pfliiger's Arch., 1878, vol. IS, p. 503. 

INDICATIONS FOR DIAPHORESIS 

Diaphoresis may be employed for the purpose of removing water 
from the body or to bring about an excretion through the skin of 
substances ordinarily excreted by the kidney. In addition to these 
scientifically well-grounded indications, diaphoresis is frequently em- 
ployed empirically to meet various others, — as, for example, in the 
beginning of infectious diseases, with the idea of securing the elimina- 
tion of bacterial toxins, or in a number of mild febrile affections, 
such as bronchitis, etc., to "bring them to the surface." It is prob- 
able that the experience, that in many infectious diseases improve- 
ment often starts simultaneously with the appearance of profuse 
sweating, has led to the belief that the improvement in the patients is 
due to this. 

Ix Renal Disease. — On the other hand, the excitation of profuse 
diaphoresis is of proven value in acute or chronic renal insufficiency, 
as the vicarious secretion through the skin, which in the course of 
a thorough sweating may remove large amounts of water, urea, NaCl, 
etc., from the body, helps to relieve the kidney. 

It is no unusual clinical experience to see, in cases with insufficient 
or suppressed renal secretion and impending uraemia, an improved 
diuresis follow a thorough sweating, and this, too, independently of the 
mechanical relief secured, — such, for example, as relief of the com- 
pression of the renal veins by ascites. This reminds one of the fact 
mentioned on page 356, that an excess of salts in the blood may cause 
a lessening of the renal secretion, which may be relieved by with- 
i I rawing salt from the diet. The removal of salt from the body by 
sweating may have a similar favorable effect. 

Sweating may also be employed as a measure of last resort to 
remove fluid in dropsical conditions, but in connection with the use 
of pilocarpine in cardiac patients it is important to remember that 
this drug may cause collapse. 

The effects produced by pilocarpine when employed as an " absorb- 
ent," for the purpose of aiding in the absorption of exudates or of 
extravasations of blood in the anterior chamber of the eye or of cloudi- 
ness in tin' vitreous humor, probably depend on the temporarily 
increased concentration of the blood which may result from sweating, 
even when the water content of the tissues is so low that diuretics 
fail to act. 

SUPPRESSION OF THE SECRETION OF SWEAT 
Atropine in doses of 0.5-1.0 mg., usually given hypodermically 

[?Tr.], nuiy be employed with advantage for the purpose of sup 

pressing profuse sweating, such as the { 'night-sweats" of consump- 



376 PHARMACOLOGY OF SECRETION OF SWEAT 

tives. As the very first expression of the action of atropine is the 
inhibition of various glandular secretions, such doses may accomplish 
this without necessarily causing' any other atropine effects except 
some dryness of the mouth and throat, but if the dose be increased 
or often repeated the other atropine effects may prove very disturbing. 

Agaricm. — Agaricinic acid, which is obtained from the white agaric 
(Polyporus officinalis), long known to possess antihidrotic properties, acts on 
the secretory nerve-endings like atrophine. This is the active substance contained 
in the impure commercial preparation known as agaricm, which is often used in 
the treatment of the night sweats of phthisis (0.005-0.01 gm. for single doses, 
0.1 gm. maximum dose for 24 hours). It has been shown by Hofmeister that this 
substance, which in large doses acts as a narcotic but which otherwise is not 
pharmacologically related to atropine, exerts a weak, atropine-like action on the 
sweat secretion and does this in relatively non-toxic doses. Under its influence 
sweating does not occur as it usually does when a cat's paw is kept warm. This 
effect is peripherally induced, for after agaricin stimulation of the sciatic is 
ineffective. On account of its local irritant action, agaricin cannot be adminis- 
tered hypodermic-ally. 

Camphoric acid, obtained by the oxidation of camphor, in doses 
of 1-2 gm. is also employed to prevent night-sweats, but no experi- 
mental investigations of its efficiency have been made (Vejux Tyrode). 

Astringents, such as tannic acid and astringent antiseptics, may be 
useful in relieving local hyperhidrosis. 

BIBLIOGRAPHY 

Hofmeister: Arch. f. exp. Path. u. Pharm., 1S88, vol. 25, p. 189. 

Vejux Tyrode, M. : Arch, intern, de Pharmacodynamic, 1908, vol. 18, p. 393. 



CHAPTER XII 

PHARMACOLOGY OF THE METABOLISM 
GENERAL CONSIDERATIONS 

In the living body there is a constant change taking place in the 
forces and. substances which form and maintain it. The organism 
is able to maintain itself and keep its weight and chemical composition 
constant, except for occasional variations, only by periodically ab- 
sorbing and assimilating material to replace that constantly lost by 
disintegration and death of its tissues, for living matter is constantly 
dying. TVe speak, therefore, of metabolic balance and equilibrium 
and of positive and negative metabolic balance, depending on whether 
or not assimilative or dissimilative phenomena are preponderant. All 
the chemical substances constituting the body take part in the tissue 
change, the inorganic mineral constituents which largely constitute the 
framework of the body taking the least active part in these changes, 
but still taking some part therein. Therefore all the constituents of 
the body must be constantly replaced to some extent if the organism 
is to survive (law of the minimum). Naturally the most active 
metabolism is that of the readily oxidized organic substances, of 
which the proteids, fats, and carbohydrates are the most important, 
for these, on account of their oxidizability, are at once the creators 
and the victims of the chemical energy, which enters the body with 
them only to leave it almost entirely in the form of heat and work. 

The chemical processes of oxidation and decomposition are in 
theory of two types : 

1. Decay of protoplasm as the result of the naturally limited life 
of all cells, the tissue change of death or of wear and tear, which 
takes place without regard to the energy which thus unavoidably 
becomes available. This is especially apparent in the decay of the 
epithelium of the skin and similar tissues and in that of the nuclear 
constituents, both of which are, from a caloric point of view, of minor 
significance. 

2. Decomposition of the replaceable constituents of the protoplasm 
for the purpose of supplying the energy (heat and force) necessary 
to life. This is functional tissue change, or metabolism of work, 
which occurs without combustion of the formed elements. In general 
this corresponds to the metabolism of nutrition, it being, in other 
words, the combined result of dissimilation or catabolic (splitting) 
processes and of assimilation or anabolic (synthetic) processes in the 
cells of the body, and is in rapidity and extent by far the more im- 
portant type of tissue change. 

The total metabolism, therefore, renders possible the transfor- 
mation of energy in the body, which may be measured directly by 

377 



378 PHARMACOLOGY OF THE METABOLISM 

determining the caloric intake and output or indirectly by determining 
the consumption of oxygen and the output of carbon dioxide. (For 
methods, Magnus-Levy, Durig.) 

The amount of the energy transformed varies within wide limits, 
being governed by external and internal conditions influencing the 
organism and by the work performed. A certain minimum is, how- 
ever, necessary to maintain the body temperature, the heart's action, 
respiration, etc., and, if the functional metabolism caunot supply 
this, the tissues themselves are consumed. A sharp distinction can, 
however, not be drawn between these two sources of supply, for reserve 
material is stored up in the different organs, which, in case of insuffi- 
cient nutrition, is rendered available for oxidation, and in the fol- 
lowing order, first carbohydrates, second fats, and last of all pro-' 
teids. Only when this reserve supply has been consumed does a 
rapid destruction of cells begin. 

The measurement of the energy transformed furnishes a general 
gauge for the momentary tissue change, but gives no indication of the 
manner or extent to which each of the three main food-stuffs, proteids, 
carbohydrates, and fats, take part in this process. With the total 
transformation of energy remaining constant, it is possible for these 
three mainstays of metabolism to be involved in very different pro- 
portions, for they can, within certain limits, replace one another in 
accordance with their caloric values, an abnormally increased or 
diminished decomposition and oxidation of one constituent of the 
body being compensated for by the opposite behavior of the others. 
As here it is a question of equivalent quantities, not in terms of mass 
but in those of caloric values (according to Buhner in round figures 
100 gm. fat = 230 gm. glycogen = 230 gm. dried muscle proteid or 
980 gm. lean meat), the body may gain or lose in the mass of its 
organic constituents, while a constant amount of energy is trans- 
formed, according as it retains or consumes larger amounts of carbo- 
hydrate or smaller amounts of fat, which are, however, calorically 
equivalent. On the other hand, the mass of material, — i.e., the body 
weight — may remain constant and energy be lost if, for example, 100 
gm. of fat be consumed and 100 gm. of carbohydra.te be assimilated. 
Determinations of the energy transformed consequently can indicate 
only the extent of tissue change, but cannot show whether the tissue 
balance is positive or negative. The much-used expression, "stimula- 
tion of metabolism," is therefore in no sense an exact one, for it may 
signify — and this is the usual meaning in therapeutic literature : 

1. An increased transformation of energy, — i.e., increased heat 
production and increased functional activity of the organs, resulting 
in an increase in the intensity and speed of all the phenomena of life 
and of decay. In other words, it may mean that in a given time more 
oxidizable material is consumed without considering for the time 
any change in the energy balance. If one assumes with Rubner 
that each and every cell protoplasm during its life is capable of 



GENERAL CONSIDERATIONS 379 

transforming' a certain amount of energy, and that, after performing 
a given amount of work, it is used up and disintegrates, it is evident 
that a therapeutic acceleration of the transformation of energy will 
bring about a more rapid dying off of cells already feeble from old age 
or otherwise pathologically weakened, and that thus the new growth 
of the healthy younger generation replacing them may be accele- 
rated. In this fashion purification and regeneration may be brought 
about and the useless elements be removed from the body. The utility 
of all those therapeutic agencies, which in an indirect fashion tend 
to increase the transformation of energy, probably depends on their 
power of inducing such regeneration. Among such measures stimu- 
lation of the skin, sea-bathing, climate,* sports, and massage may be 
mentioned. In so far as they facilitate or stimulate muscular activity, 
the stimulants of the central nervous system may be considered as 
doing this. Among these are strychnine, caffeine, alcohol in small 
amounts, — in short, all those drugs known as "excitantia nervina," 
or nerve stimulants. 

Disappearance of Pathological Tissue as a Result of General 
Acceleration of the Transformation of Energy. — Such a regenerative 
selection — that is, an extermination of less resistant, degener- 
ated, or otherwise weakened body cells — may be accomplished by 
chemical or physical forces, which, while reaching all or most cells 
in equal intensity, exert on them an action supported without apparent 
damage by healthy cells, but fatal to unhealthy ones. This may be 
compared to the way in which it is possible by the application of such 
mild caustics as lactic acid to destroy diseased tissue without harming 
the healthy tissue necessarily submitted to the same treatment. Of 
the agencies acting in this fashion the physicochemical ones, heat and 
radiant energy, may be considered as having such effects, though only 
to a limited extent. Variations in the osmotic tension of the tissue 
cells — that is, in their water and their salt content — produce such 
effects to a marked extent. This is the basis for the various popular 
blood-purifying cures, water cures, thirst cures, and so forth. 

Specific Alteration of Metabolism. — While an alteration of osmotic 
conditions affects all the cells of the body as a whole, and by physico- 
chemical "mass action" disturbs the chemical equilibrium of nil of 
them, considered as elementary organisms, and alters their function, 
there are also purely chemical agents, which in a more delicate man- 
ner, that is not susceptible of a further analysis, accelerate or retard 
only certain of the chemical reactions of protoplasm, without otherwise 
altering its slrncture or function. These may be looked upon as 
specific catalyzers of the metabolic processes, to which we reckon the 
products of certain glands, especially that of the thyroid and, in a 
limited and opposite way, quinine. 

2. Stimulation of the metabolism indicates quite another thing 
when tin- object is to secure an increased assimilation of material, 

* Son Loewy v. Fr, Milller. 



380 PHARMACOLOGY OF THE METABOLISM 

whether this means a more rapid and greater increase of weight 
in young, rapidly growing individuals or the attainments of a better 
state of nutrition in badly nourished adults, such as invalids or con- 
valescents. Here the indication is not to accelerate the transformation 
of energy by increasing catabolic processes, such as oxidation and 
cleavage, but rather to moderate it as far as possible or to over- 
compensate for it. As a matter of fact, in such cases the transfor- 
mation of energy is, as a rule, augmented, while proteid is assimilated 
and retained as organ proteid. In addition to purely dietetic measures 
and those which improve the appetite and the digestion and absorp- 
tion, such as forced feeding, with exercise, a number of pharmacologi- 
cal agents may produce these effects by specifically influencing tissue 
change in such fashion that assimilation — that is, the synthetic for- 
mation of new body substance — is stimulated, and a condition results 
similar to that of the youthful growing organism (Hoffstrom) or to 
that of an individual convalescing from an exhausting disease (Liithje 
u. Bcrgcr). Of the manner in which such effects are produced little 
is known up to the present. 

When the action is more pronounced or when toxic doses are given, 
these same substances act harmfully on the protoplasm of the cells, 
causing their rapid death and accelerating their disintegration. Under 
certain conditions both the favorable and the destructive actions may 
occur simultaneously in the body as a result of the variable resisting 
powers of the cells of the body. This may explain many specific 
curative actions. 

Furthermore, such actions on metabolism, partly conservative 
and partly harmful, may be so feeble or may be limited to such small 
especially susceptible portions of the body that they cause no observ- 
able effects on the general metabolism and therefore cannot be meas- 
ured. However, clinical observation of resulting changes in the 
distribution of material in the body, such as the absorption of exu- 
dates, tumors, or connective-tissue growths, can give sufficient evidence 
to permit the assumption of such actions on the metabolism. The 
substances producing such results will be considered later in the 
group of inhibitors of oxidation (p. 404). 

3. Finally, an alteration of metabolism may be considered, 

WHICH AFFECTS CHIEFLY OR ENTIRELY ONLY CERTAIN CONSTITUENTS OB 

decomposition products of the protoplasm of the body. This there- 
fore demands a special discussion.* 

* This general discussion and division under 1, 2, and 3 are schematic and to 
a certain extent arbitrary, for they include only some of the pharmacologically 
interesting phases of metabolism. 

In physiology it is customary to differentiate between the tissue change neces- 
sary for maintenance of metabolism during rest, i.e., the energy transformation 
occurring in a fasting human being during complete inactivity, and the augmen- 
tation of metabolism resulting from definite work performed by the organs — 
functional metabolism. The metabolism during rest, however, in addition to the 



GENERAL CONSIDERATIONS 381 

In so far as the function of the cells is under central nervous 
control, it is clear that their metabolism also may be indirectly in- 
fluenced through the central nervous system, for every functional act, 
every cell activity, depends on a catabolic change, which is quickly 
followed by a compensating — often, in fact, by an over-compensating 
— restorative process. This reaction resulting in compensation or 
over-compensation is one which we are not yet able to analyze or 
understand. Like the capacity for growth, it is an essential character- 
istic of living matter. 

The stimulation of growth, with assimilation of proteid, which con- 
tinued and violent muscular exercise causes is the best example of such 
over-compensation (Caspari, Loewy, Bornstein) . The increased blood 
and food supply brought to the organ as a result of its functional 
activity doubtless is a. factor, but only a partial factor, in this result. 
On the other hand, organs forced to remain inactive undergo atrophy. 

The chemical regulation of the body temperature (see Chapter XV) 
is another instance of a. metabolic process controlled by the nervous 
system, which demands special separate consideration. 

BIBLIOGRAPHY 

Bornstein: Pfliiger's Arch., 1901, vol. 83. 

Caspari: Pfliiger's Arch., 1901, vol. 83. 

Durig: Ueber den Erhaltungsumsatz. Akad. d. Wiss. Wein., 1909, vol. 80, p. 110. 

Hoffstrom: Acad. Abli. der Universitiit Helsingfors, Leipzig, 1910. 

Loewy: Dubois' Arch., 1901. 

Loewy u. Fr. Miiller: Ztschr. f. Balneologie, Klimatologie, etc., 1910, vol. 3, p. 1. 

Loewy u. Fr. Miiller: Ztschr. f. exp. Path. u. Ther., 1909, vol. 7. 

Liithje u. Berger: Deut. Arch. f. klin. Med., 1904, vol. 81, p. 278. 

Magnus-Levy: Noorden's Handb. d. Path. d. Stotfw., 1900, vol. 1, p. 200. 

Aside from these indirect influences through the central nervous 
system, all physical or chemical stimuli which act directly on the cells 
of the body must influence their chemical activity, and thus affect the 
transformation of matter and energy in them. For reasons of prac- 
tical import, it is advantageous to start the discussion of such direct 
influences with that of — 

purely vegetative tabolism <>f decay, includes ;i large portion of the functional 

metabolism, as it necessarily includes the metabolism resulting from* the activity 
of the heart, of the respiratory system, and of the glands, as well as that 
involved in the production of beat. These two components, however, are in- 
fluenced by pharmacological agents in very different degrees and in opposite 
directions. Drugs which, like arsenic, influence the metabolism of decay, affecting 
the duration of the life of the cells, do not necessarily produce an appreciable 
alteration in the metabolism of function. On the other hand, drugs affecting 
function, -neb as the narcotics, or those acting on nerves or on the- heart, fir., 
.-,- a general rule do nol affed the metabolism of decay, although they primarily 
Increase or decrease the transformation of energy and material, the functional 
metabolism, only of the organs whose activity is stimulated or depressed. For 
these reasons the appreciation of the difference between metabolism of decay 
and metabolism of function appears essential to the proper understanding of the 
manner in which drugs produce alterations in the metabolism. 



382 PHARMACOLOGY OF THE METABOLISM 

i. THE TEMPERATURE OF THE BODY 

It is well known that an increase in the temperature causes an 
acceleration of the rate at which all chemical reactions take place. 
According to van't Hoff, a rise of 10° C. almost doubles or trebles 
the rate of reaction. Within certain limits of temperature the same 
holds good for biological phenomena (Linser and Schmid, Matthes, 
Kanitz), every rise in the body temperature beyond the normal in- 
creasing and accelerating the metabolism, while marked lowering of 
the body temperature retards and lessens the metabolism (Bumpff). 

Such overheating or cooling of the body may indirectly result from the 
action of drugs which, like cocaine, tetrahydronaphthylamine, and atropine, excite 
the centres controlling the hert regulation, or which, like the narcotics, especially 
alcohol and chloral and the antipyretics, depress them. (See Loewi and also 
Chapter XV.) 

BIBLIOGRAPHY 

Kanitz, Aristides: Z. f. Elektrochemie, 1907, No. 44. 
Linser u. Schmid: Deut. Arch. f. klin. Med., 1904, vol. 79. 
Loewi: v. Noorden's Handb. d. Path. d. Stoffw., 1907, vol. 2. 
Matthes: Handb. d. Path. d. Stoffw., 1907, vol. 2. 
Rumpff: Ptluger's Arch., 1881, vol. 33. 

2. LIGHT AND RADIANT ENERGY 

Natural illumination indirectly exerts an influence on the metabo- 
lism, inasmuch as through the eye it constantly sends sensory im- 
pulses to the central nervous system, as a result of which, muscular 
tension and movements are excited and possibly also other vital 
processes, — for example, the formation of the red blood-cells {Marti u. 
Kronecler) . 

As far as has been proven, however, only the blue-violet and ultra- 
violet rays exert a direct influence on the chemism of the cells of 
the higher animals. These rays exert a destructive action on enzymes 
and on living protoplasm, just as they do on all chemically labile 
substances. This power is systematically employed in phototherapy, 
in the treatment of lupus, cancer, etc., according to such methods as 
that of Finsen, and by means of especially adapted sources of light. 

Of a similar nature is the action of the luminous energy absorbed 
by fluorescent substances. Such substances as quinine, eosine, acridine, 
etc., when charged with this energy, as long as they remain exposed 
to light decompose living protoplasm and other very susceptible sub- 
stances, such as enzymes, toxalbumins, etc. According to v. Tappeiner 
and Jodlbauer and to Strauh, ionized oxygen is probably the active 
agent in this destructive action. In therapeutics this property of these 
substances may be utilized by such methods as painting 0.1-0.5 per 
cent, eosin solution on those portions of the surface of the body where 
a corrosive effect is desired and exposing them to sunlight. 

As a result of their absorption by fluorescent substances, the yel- 
low and red light waves, which ordinarily are inert chemically, may 



LIGHT AND RADIANT ENERGY 383 

be rendered chemically active, and, as these rays penetrate vegetable 
and animal tissues more readily than the violet ones, it is perhaps 
possible for them to produce effects in the interior of the body if the 
tissues are impregnated with yellow or red fluorescent substances. 

Haematoporphyrin, a haemoglobin derivative almost constantly found in 
human urine, is markedly fluorescent, and under the influence of light exerts 
marked hemolytic actions. It is probably constantly present in the mammalian 
organism, although normally the amount present is extremely small. If abnormal 
amounts of it appear in the blood, those portions of the skin which are exposed 
to the sun may become diseased. This is probably the cause of the skin lesions 
in hydroa eestiva (Hausmann) . It also appears probable [? Tr.] that a photo- 
dynamic substance present in the corn consumed is of significance in connection 
with the skin lesions of pellagra (Horbaczewslci, Raubitschek, Hausmann). 

Rontgen Rays and Radium Emanations. — Finally, mention 
should be made here of the similarly destructive action of X-rays and 
of radium emanations. On account of their power of penetrating the 
soft parts of the body, their action is not confined to the surface, but 
also affects the blood and tissues in the interior of the body. Ex- 
posure to them results in a destruction of the red cells and accumu- 
lation of pigment in the body, and more especially in a very extensive 
destruction of myelocytes and lymphocytes and of lymphoid tissue. 
This latter action has been utilized in the treatment of leukaemia. 
Other cells also of embryonal type, such as the germinal cells of the 
sexual organs and the cells of pathological new growths, are readily 
affected and destroyed. This destruction of cells results in an in- 
creased decomposition of proteid and increased excretion of nitrogen. 

Radio-active Waters. — Radio-active minerals and earths, such as 
the uranium slag from the mines of Joachimsthal, when placed in 
water, give off radio-active emanations to it. Consequently the waters 
of many springs are naturally radio-active, while ordinary water 
may be made so by being kept for many hours in contact with radio- 
active material. 

Although it is highly probable that the radio-activity of baths 
and drinking waters can exert an influence on the human organism, 
this cannot be asserted positively. Clinical experience, however, has 
led to the belief that radio-active waters exert a beneficial action on 
rheumatic and other similar conditions. It has been possible to cause 
a disappearance of uric acid from the blood of gouty patients and 
to relieve their gouty symptoms by causing them, for several hours 
daily and for several weeks, to inhale air charged with radium 
emanations. According to Oudzcnt, sodium urate is changed by them 
into other more soluble substances. This, if true, would explain the 
absorption of the uratic deposits and the disappearance of uric acid 
from the blood. (Sec also His, Richet, Loewenthal u. Wohlgemuth.) 

Nothing is known aboul the dired ad ion of electric energy on the 
metabolic pro© sees of the cells. 



384 PHARMACOLOGY OF THE METABOLISM 



BIBLIOGRAPHY 
Bcil u. Baubitschek : Wien. klin. Woch., 1910, Xo. 2G. 
Gudzent: Med. Klinik, Xo. 42. 
Hausmann, W.: Wien. klin. Woch.. 1910, Xo. 36. 
Hausmann: Die sensibilisierende Wirkung des Hiiniatoporphvrins. Biochem. z., 

1910, vol. 30, p. 270. 
Heinecke: Mitt. a. d. Grenzgeb. d. Med. u. Chir., 1905, vol. 14. 
His: Med. Klinik., 1910, Xo. 16. 
Horbaczewski : Oesterr. Sanitiitswesen, 1910, Xo. 31. 
Jodlbauer: Jahrber. Leist. d. physik. Med., 1908, vol. 1, p. 280. 
Loewenthal u. Wohlgemuth: Biochem. z., 1909, p. 470. 
Marcacci: XII Kongr. Assoc, med. Ital., 1887. 
Marti u. Kronecker: Verh. d. XV Kongr. f. inn. Med., 1897. 
Bichet: Arch, intern, d. Physiol., 1905, vol. 3, p. 130. 
Straub: Arch. f. exp. Path. u. Pharm., 1904, vol. 51. 
v. Tappeiner u. Jodlbauer: Die sensibilisierende Wirkung floureseieren der Sub- 

stanzen, Leipzig, 1907. 

3. WATER AND SALT ACTIONS 

Osiiotic Tension. — If a certain number of gas molecules are in- 
troduced into a vacuum with elastic walls, they seek to increase the 
volume of the vacuum by distending the walls. The degree of this 
gas pressure is proportional to the number of molecules in the unit 
of space, their concentration, and to the absolute temperature. If a 
given number of molecules or ions are introduced into a quantity of 
water surrounded by elastic walls, they too tend to increase the 
volume of the water and to distend the containing walls, which absorb 
the water on the outside and allow it to enter into the water contained 
within them. This water absorbing or attracting pressure is, like the 
gas tension, proportional to the concentration of the molecules or ions 
in solution and to the absolute temperature. The passage of water 
through the membrane is called osmosis and the pressure exerted is 
called osmotic pressure or tension. Gas tension and osmotic tension 
are analogous. 

Isotonicity. — As all the protoplasm of the cells of the animal 
body is more or less permeable to water and is bathed in watery 
media, such as lymph, blood-plasma, etc., it follows that the osmotic 
tension — i.e., the molecular concentration of the substances which 
exert osmotic tension — must be the same in the cells and in the sur- 
rounding media, for otherwise the volume of the cells would be con- 
stantly changing. The cells and the surrounding media must be 
isosmotic or isotonic to each other. Actually this is approximately the 
case, all the living cells of the mammal having the same osmotic tension 
as the fluids present in its tissues. This tension corresponds closely 
to that of 0.9 per cent. NaCl solution, 0.154 mols, per litre, 1 mol or 
gramme molecule equalling 58.5 gm. NaCl, This osmotic tension is 
due only in the slightest degree to colloid substances (proteids, etc.), 
being almost entirely determined by dissolved crystalloids, chiefly salts 
(the chlorides, carbonates, and phosphates of the alkalies). 



WATER AND SALT ACTIONS 385 

The colloids may be looked upon here as forming a sort of membranous 
framework which pervades the cells, its outer layers forming an external 
membranous shell which may be considered as concentrically continued into the 
interior of the cells. Most animal cells lack a specially differentiated cell 
membrane. 

If the osmotic tension of the body fluid be altered by the introduc- 
tion of water or of salts, a difference of tension between them and the 
tissue cells results, and the latter will contract or swell up according 
as the tension is increased or diminished. However, if the colloids 
of the cell are equally permeable to the molecules in solution (salts, 
etc.) and to water, or equally impermeable to both, its volume will 
remain unchanged, in the first case because no difference in tension 
arises and in the second because the impermeable walls prevent any 
equalization of the tension. 

Slight differences in tension, such as arise during the changing 
play of the absorption and excretion of substances, are compensated 
for by the cells without harm, just as is the case with other normal 
variations in the conditions of life, but more pronounced and espe- 
cially rapidly produced alterations of osmotic tension cannot be sup- 
ported without injury. 

A quite gradual, even though very decided, increase of the osmotic tension 
of the surrounding medium may be supported by vegetable cells, and appaiently 
even by animal cells, for they are able to accommodate themselves to higher 
than normal osmotic pressure if it is produced gradually enough. 

Alterations of the osmotic pressure, which under some circum- 
stances do more or less damage to the cells, may be produced by the 
introduction of large quantities of pure water or of salts. The effects 
on the metabolism express themselves by an increased excretion of the 
decomposition products of proteids, especially urea. 

PHARMACOLOGICAL ACTIONS OF WATER 

Local Effect. — Pure water is a violent poison for organism 
whose cells are very readily permeable to it. If cephalopods be im- 
mersed in distilled water, convulsive movements occur and death 
ensues in 5-10 minutes (Phisalix). 

Injection of water directly into the circulation is followed by the 
passage of haemoglobin into the plasma, as some of the red blood-cells, 
the less resistant ones, are destroyed: 100-150 c.c. per kilo will 
quickly kill dogs and rabbits, while even 30 c.c. can produce fatal 
results in a few days (Bosh u. Vedel). 

On the other hand, cells which are less permeable are much more 
resistant to pure water. However, the disturbing toxic action of 
pure water is evidenced even in the mouth by a flat, disagreeable 
taste and in the nasal and pharyngeal mucous membranes by a dis- 
tort ion of their cells when pure water is applied to them. Pre- 
sumably the superficial epithelium of the gastric and intestinal mucosa 
25 



386 PHARMACOLOGY OF THE METABOLISM 

may be similarly affected, and there may thus result an accelerated 
casting off and renewal of these cells. It is possible that such effects 
may play some role in the treatment of gastric catarrhs by lavage 
with plain water, or by the drinking of indifferent waters, such as 
those of Gastein, Wildbad, and many other springs. 

If the water is absolutely pure, it is claimed that the local osmotic action 
may be so great that serious irritation of the stomach may result. To such 
effects Koppe attributes the harmful effect of swallowing natural ice, which, 
in contradistinction to artificial ice, contains extremely small amounts of salts, 
and also that resulting from drinking the waters of the " poison spring " in 
Gastein. Whether this explanation be correct or not is uncertain. 

The healthy gastric epithelium is almost impassable for water and 
for salts, and therefore within wide limits is unaffected by the 
osmotic tension of the gastric contents. Considering the fact that 
food, etc., must often remain for a long time in the stomach, it is 
easy, from a teleologic point of view, to recognize the advantage 
of this insusceptibility. We owe our knowledge of the fact, that 
water and substances dissolved in water are hardly at all absorbed 
by the gastric mucosa, originally to Hirsch, whose results have been 
confirmed by v . Mering and by Brandt. 

If water contains alcohol or C0 2 , it is absorbed from the stomach. 
It is not known whether these substances to a greater or less extent 
loosen the lipoidal cement between the epithelium or whether they 
render the epithelium more permeable in other indirect ways. 

In the intestines water is rapidly absorbed, and, as a rule, is al- 
most completely excreted by the kidney in the course of several 
hours. 

Effects After Absorption. — It is self-evident that, so long as it 
remains in the blood and the tissues or is passing through them, pure 
water will reduce their osmotic tension, but when water is taken at 
the same time with food, even when several litres are taken, it causes 
such slight changes in the osmotic tension that it does not appreciably 
increase tissue change. If, however, large amounts of water are drunk 
during a period of fasting, its effects on the osmotic tension of the 
body fluids may result in an increased decomposition of proteid and 
of fats and carbohydrates (Heilner). 

It is not possible to form any opinion as to whether or not such a 
stimulation of metabolism and regeneration plays any role in the 
effects of the water-drinking cures which have been widely used in the 
treatment of many chronic diseases, such as syphilis, gout, metallic 
poisonings, etc. In any case, the augmented blood and lymph flow, 
which necessarily result from the drinking of large amounts of water, 
must be of some significance for the " flushing out" of the body and 
the removal of metabolic end products. 

"While the flooding of the body by water may be counteracted by 



WATER AND SALT ACTIONS 387 

increased diuresis, diaphoresis, etc., the converse of this — the removal 
of water, or dehydration, by thirst cures — causes an osmotic alteration 
in the opposite direction, which cannot be relieved by physiological 
regulation, and consequently its effects in favoring the destruction 
and regeneration of various cells are more energetic and persistent. 
In Straub's experiments the increased nitrogen excretion persisted 
for some days after abandoning the limitation of the water intake 
(for lit. Mag mis-Levy, Dennig). 

BIBLIOGRAPHY 

Bosk et Vedel: Arch, de Physiol, norm, et path., Oct., 1896. 

Denning: Ztschr. f. diat. Ther., 1899. 

Heilner: Ztschr. f. Biol., 1907, vol. 49. 

Hirseh: Zentralbl. f. kl. Med.. 1892, No. 47. 

Hirsch: Zentralbl. f. kl. Med., 1S93, No. 4, 18, 29. 

Koppe: Deut. med. Woch., 1898, No. 39. 

Magnus-Levy: Handb. d. Path. d. Stoffw., 1906, vol. 1, p. 443. 

Phisalix: Arch, de Physiol, norm, et pathol., 1892, series 5, vol. 4, p. 217. 

Straub: Ztschr. f. Biol., 1899, vol. 38. 

PHARMACOLOGICAL ACTION OF NEUTRAL SALTS 
Such effects are produced in the purest form when water is ab- 
stracted from the tissue cells by the administration of salts in sub- 
stance or in hypertonic solution. This has been experimentally 
proven for sodium chloride, nitrates, acetates, and carbonates (lit. 
Eost), and doubtless holds good for all crystalloids which are ab- 
sorbed by the blood, in so far as the tissue cells are not readily 
permeable to them and therefore will be affected by changes in the 
osmotic pressure produced. The exact manner in which the cells are 
damaged is not known, but it should be remembered here that 
chemical cleavage reactions may be caused by dehydration through 
osmotic action, — for example, fibrin may be dissolved with the for- 
mation of globulin and albumoses {Limbourg, Dastre). 

Accordingly, it is more than probable that when large quantities 
of sodium chloride, or readily absorbable salts, such as potassium 
iodide or bromide, are administered, a portion of the curative effects 
obtained may be attributed to an osmotic stimulation of metabolism 
and cell regeneration. However, the portion of the curative effects 
thus produced can hardly be very large, for these substances are 
usually taken with large amounts of water. Moreover, their osmotic 
action will be limited further by the fact, still unexplained, that the 
administration of salts actually causes a limitation or retardation of 
proteid metabolism, if enough water is taken at the same time with 
the salts to prevent any dehydration of the cells {Host). Such a 
retardation or limitation of the catabolism in protoplasm has been 
proven to result from the administration of different sodium salts. 
Inasmuch as osmotic action — i.e., a dehydrating action — has been 
excluded, such effects can be due only to an ion action, and in this 



388 PHARMACOLOGY OF THE METABOLISM 

case only to the action of the sodium ions, whose concentration in 
the organism has been increased while that of the other cations. 
K', Mg', Ca', etc., present in the body has not been altered. 

From the fundamental investigations of Loeb, Overton, and others, we 
know that any alteration in the normal cation proportions markedly influences 
various vital phenomena. If this interpretation be correct, the administration 
with water of corresponding amounts of the salts contained in Ringer's solution * 
should cause no sparing of proteids or nitrogen retention. Otherwise the above- 
mentioned effects would be due only to a dilution of the colloids and alteration 
of the viscosity, the effects of which on the vital processes are still unknown. 

A secondary result of the administration of neutral salts is the 
loss of alkalies by the body. Salts which are absorbed with difficulty 
(the cathartic salts, salts of polybasic acids), as a result of their 
cathartic action, cause a loss of the alkaline intestinal juices, while 
readily absorbable salts (those of the sodium chloride group and 
salts of the monobasic acids) cause a distinct but much smaller loss 
of alkalies in the urine, for this secretion becomes more and more 
strongly alkaline with increasing salt diuresis (Riidcl). "Whether or 
not the continued use of large quantities of neutral salts results in 
any damage to the organism is doubtful, for the body possesses the 
means of protecting itself against loss of its alkalies (see below). 

All the same, in this connection it is noteworthy that the long-continued 
use of the natural alkaline cathartic waters is better borne than that of the 
neutral ones, and that the continued use of strongly salted food appears to cause 
a disposition to disease (scurvy), which may be overcome or lessened by the 
consumption of fresh vegetable juices, such as lemon juice, etc., which contain 
salts of the vegetable acids with alkalies, which are combusted in the body 
with the formation of carbonates and therefore act like the alkalies. It is, 
however, more likely that this curative effect in scurvy is due to the potassium 
ions present in the vegetable juices antagonizing the poisonous action of the 
sodium ions with which the body is flooded as a result of consumption of salted 
foods ( Emmerich ) . 

The salts of the Glauber's salt group, which are absorbed with 
difficulty, influence the metabolism in general only in so far as they 
cause catharsis and thus interfere with the utilization of the food. 
However, the bitter waters (magnesia waters), even when taken in 
small non-cathartic doses, diminish the absorption of the fats 
{V allien), probably on account of the formation of insoluble soaps 
with magnesia. 

To a slight extent the cathartic salts are absorbed in the small 
intestine, and of this amount a portion is excreted again into the 
large intestine {Hay). It is clear that during this passage through 
the portal circulation these salts may exert a " salt action " on the 
cells of the liver and the intestines, and this may in part account for 
their favorable effects in diseases of the intestines and liver. 

* Ringer's solution for mammals contains 0.9 per cent. NaCl, 0.03 per cent. 
NaHC0 3 , 0.042 per cent. KC1, 0.24 per cent. CaCh. 



ALKALIES 



BIBLIOGRAPHY 

Dapper u. v. Noorden: Hdb. d. Path. d. Stoffw., 1907, vol. 2. 

Dastre: Arch, de Physiol., 1895. 

Emmerich: Pfliiger's Arch., 1870, vol. 3. 

Hay: Journ. of Anat. and Physiol., 1882. 

Limbourg: Phys. chem., 1889, vol. 13. 

Loeb, J.: Biochem. Ztschr., 1911, vol. 31, p. 450. 

Eost: Arb. d. Kais. Ges., 1901, vol. 18. 

Rudel: Arch. f. exp. Path. u. Pharm., 1892, vol. 30. 

Vahlen: Ther. Monatshefte, 1898, vol. 12. 

ALKALIES 

Among the salts, those reacting alkaline occupy a special position. 
Such are the basic salts or the salts of the weak acids such as the 
carbonates. The free alkalies, in respect to their action in the 
organism, are also to be considered as belonging to this group. 

In this connection the basic phosphates and the carbonates, the 
weak alkalies, such as Ca(OH) 2 and Mg(OH) 2 , the salts of the 
alkalies with vegetable acids, which are oxidized in the organism to 
carbonates, and, finally, the borates are of practical importance. 

Reaction of the Blood. — Blood and lymph always contain large amounts 
of indifferent carbon dioxide, of which a portion is present in the form of 
carbonic acid, corresponding in amount to the quantity of the alkalies in 
solution. Therefore in a theoretical sense blood and lymph are necessarily 
neutral.* 

Potentially, however, the blood is both acid and alkaline, and may be 
stated to be amphoteric, inasmuch as, without losing its theoretically neutral 
reaction, it may absorb acids or alkalies, in the first case the C0 3 ' ions being 
liberated from their original combinations, in the second, the C0 2 which is 
always present being utilized to combine with the bases absorbed. Moreover, 
not only the carbon dioxide but also the latent H' ions of the blood proteids 
may be brought into action by the addition of alkalies, while, on the other 
hand, by the addition of acids both of these may again be rendered inactive or 
latent. Even in the presence of grave or fatal acid intoxication, the reaction 
of the blood consequently remains almost normal (Benedikt, Ssili, Robertson). 
It is thus evident that the determination of the reaction of the blood by the 
use of different dyes as indicators can give only values which are physiologically 
incorrect (IT. Meyer, Henderson) . To litmus the blood-plasma, outside of the 
body, reacts alkaline, because this acid possesses a stronger affinity for the bases 
than carbonic acid and the acid proteids of the plasma, and consequently deprives 
them of their alkalies, with which it forms blue-colored salts. 

Increased Alkalinity. — As many chemical processes, particularly 
oxidation, — e.g., that of glucose, — are either accelerated by, or only 
possible in the presence of, free Oil' ions, it would, a priori, appear 
probable that the administration of alkalies would stimulate oxida- 
tion in the animal organism as a result of augmentation of the car- 

* Inasmuch as in the presence of ;i high CO a tension traces of free carbonic 
acid an- present in an aqueous solution, the plasma may contain traces of 
free II' ions, and consequently, theoretically, may be very slightly acid. The 
same holds true, however, also for the potentially basic proteids of the plasma, 
so that free IIO' ions may also be present, and exact determinations have 
shown that in the blood-plasma there is an exceedingly small excess of the 
free HO' ions. 



390 PHARMACOLOGY OF THE METABOLISM 

bonate alkalinity of the protoplasm. This presumption, even if it 
should be correct, is distinctly limited in its significance by the fact 
that, in the normal organism, it is not possible, even by the admin- 
istration of alkalies in large quantities, to increase the alkalinity of 
the blood for any length of time, for any carbonate in excess of the 
normal is almost immediately excreted by the kidney and the in- 
testines (Raimond, Freudberg). Moreover, it is altogether un- 
certain to what extent and how rapidly the cell protoplasm itself 
takes any part in temporary alterations of the alkalinity of the blood 
and lymph, a participation that evidently would be of essential im- 
portance. 

Action of Alkalies on Metabolism. — It has been claimed that 
the catabolism of proteids and of fats is influenced by the 
alkalies, but the experiments on animals and on men undertaken for 
the purpose of investigating such action have given contradictory 
results, which are also not free from ambiguity in their significance, 
inasmuch as the " alkali action " cannot be sharply differentiated 
from the accompanying " salt action." No specific effects on the 
decomposition of proteids, including the metabolism of purins, nor 
on the carbohydrate metabolism, have been definitely proven to result 
from the administration of alkalies, with the single exception that 
proteid anabolism is temporarily retarded, but this is compensated 
for in the later periods of the experiment. On the other hand, A. 
Loewy's experiments indicate that it is probable that the alkalies exert 
a stimulating effect on the oxidation of fat, and Rubner and Rost 
have definitely proven that the borates do exert such an influence. 

This is in agreement with the well-known reducing effect of 
Carlsbad and similar alkaline saline waters. On the other hand, it 
appears that under some conditions certain other oxidative processes 
may be inhibited by the alkalies, for following the ingestion of large 
amounts of sodium carbonate or citrate (20-30 gm. per diem) more 
" neutral " and less " oxidized " sulphur is excreted in the urine 
(Jawein). 

Alkalies in Gout. — The manner in which the alkalies produce their 
reputed favorable action in gout is still unknown. So long as it was 
believed that gout was due to a retention of uric acid resulting from 
unfavorable conditions for its solution and the consequent difficulty 
with which it could be excreted through the kidney, it was natural 
to explain the value of the alkalies by their supposed power of bring- 
ing uric acid into solution. This explanation is, however, certainly 
incorrect, for such action cannot occur under the conditions which 
obtain in the organism (Gudzent). Further, the recent exhaustive 
investigations of Brugsch and ScJiittenhelm have rendered it ex- 
tremely probable that in gout it is not the insolubility or the faulty 
excretion of uric acid, but a retardation of its formation or destruc- 
tion on account of a defective ferment activity, which is the decisive 



ALKALIES 391 

pathogenic factor. In addition, exact investigations of the effect 
of the administration of alkalies on the excretion of uric acid in 
gout have given results which are by no means lacking in ambiguity 
(v. Noorden), but in the majority of instances the excretion of uric 
acid was not affected. For these various reasons, it is exceedingly 
doubtful whether the alkalies in any way affect the metabolism, 
solubility, or excretion of uric acid. The inclination of clinicians is 
rather to explain the unquestionably beneficial action of alkalies in 
gout by their curative action on disturbances of the alimentary canal 
and the liver, which quite often are present in this disease (v. 
Noorden). 

Urolytic Action of Alkalies. — On the other hand, the value of the 
alkalies in the treatment of uratic deposits in the urinary tract is 
well established and is doubtless due to the increased alkalinity of 
the urine thus caused. This increase need not be so great as to cause 
the urine to render red litmus paper blue, but it may always be 
recognized by the relative increase of the disodium phosphate as 
compared with that of the acid monosodium phosphate. The bene- 
ficial effect of this increase in the alkalinity of the urine is evidenced 
by the fact that often after a short time small pieces of the con- 
cretions are passed out with the urine, and that very often the 
excretion of uric acid is increased (v. Noorden). Among the alkalies, 
the alkaline earths appear to be especially useful for this indication, 
and, among these, calcium appears to be the best, on account of the 
fact that it is free from any disturbing side actions, with the ex- 
ception of the very occasional formation of large fecal concretions. 

These alkaline earths, especially chalk and magnesia, combine with 
fatty acids and with sulphuric and phosphoric acids in the intestine, 
and consequently the urine becomes alkaline and at the same time 
contains less sulphates and less phosphates, — i.e., less salts, — so that 
its molecular concentration falls. This, too, is of material importance 
for the more ready solution of the urates, and sufficiently explains 
the value of these alkalies and of the waters containing them 
CWildungen, Fachingen, etc.) in the treatment of uratic deposits in 
the urinary tract (Caulet, J. Strauss). 

Effects on the Alkalinity of tiie Blood. — Although, as 
previously stated, the normal alkalinity of the blood cannot be ap- 
preciably augmented by the administration of the alkalies, it is quite 
Otherwise in the presence of abnormally diminished alkalinity of the 
blood, such as occurs in exogenous and endogenous acid intoxication. 

Carnivorous animals, and to some extent also vegetarian animals 
and man, are able to protect the alkaline carbonates and albuminates 
of their blood from decomposition by acids, by utilizing the ammonia, 
formed during the breaking down of proteids, for the neutralization 
of any abnormal amounts of acid, instead of transforming it as usual 
into carbamic acid and urea. This is the explanation for the fact 



392 PHARMACOLOGY OF THE METABOLISM 

that the quantity of ammonia excreted in the urine is invariably in- 
creased in acid intoxication of any type (Loewi). However, this pro- 
tective regulation of the organism is a limited one, and, if enough 
acid be administered or produced, it may be so inadequate that the 
carbonate alkalescence of the blood will be decidedly diminished. 

This occurs in diabetic coma as a result of the formation of oxy- 
butyric acid, or when abnormal amounts of lactic acid are formed as 
a result of excessive muscular exertion, and in many poisonings, 
such as those produced by arsenic, phosphorus, etc., and in the 
toxemia of fever. F. Eraus found the alkalinity of the blood, in 
terms of the C0 2 removable by the vacuum pump, diminished to Y* 
or % of the normal in typhoid fever, erysipelas, and scarlatina, and in 
tuberculosis with continuous fever. As this diminution of the alka- 
linity persists in such cases even when the temperature is artificially 
lowered, it is evident that it does not depend on the increased tem- 
perature but is due to the toxic decomposition of proteids. The deficit 
in alkaline carbonates in the blood and its more or less harmful 
effects may be lessened or removed by the administration of the 
alkaline salts of the vegetable acids, the citrates being especially 
adapted for this purpose, as they are almost completely combusted 
in the body with the formation of carbonates. 

Especially in severe diabetes mellitus large amounts of oxy- 
butyria acid are formed which greatly diminish the alkalinity of the 
blood by expelling the combined carbonic acid. In extreme cases, 
instead of 30-36 per cent, by volume, Eraus found only 12.4 and 
9.8 per cent of carbonic acid in the venous blood, while Minkowski 
found as little as 3.3 per cent. It is clear that in such cases the ad- 
ministration of alkalies will be beneficial and even life saving 
{Magnus-Levy) . It is claimed that calcium carbonate and phosphate 
exert an especially favorable influence in diabetes. In addition to 
their action as alkalies, their value is probably in part due to the 
fact that the diabetic appears to lose his calcium more readily than 
the other alkalies and therefore has a greater need for this particular 
element (Schlesinger u. Gerhardt.) 

Other Actions of the Alkalies. — In addition to the effects on 
metabolism discussed above, the alkalies by their local actions produce 
a number of therapeutically important effects. Concentrated potas- 
sium hydrate solutions decompose and destroy organic substances, 
even such resistant ones as the horny structures of the skin, in which 
process their power of saponifying and dissolving the protective fat 
in the skin is of more or less assistance. They are, therefore, used 
externally in different concentrations as caustics and as means of 
irritating, softening, or cleaning the skin. Vienna caustic paste, 
potassium soaps, sodium hydrate, and potash may be used as counter- 
irritants or as disinfectants in scabies. Sodium soaps are used for 
cleansing purposes or as mild irritants in enemata. Borax may be 



ACIDS 393 

employed as a lotion or in mouth washes. Internally dilute solutions 
of the alkaline carbonates or of Ca(OH),, compound chalk powder, 
magnesium oxide, may be used for the direct neutralization of acids 
in the stomach or intestines or to stimulate [? Tr.] the gastric diges- 
tion (Pawlow) or to dissolve mucus (see Pharmacology of the Diges- 
tion, p. 165). 

BIBLIOGRAPHY 

Benedikt: Pfiuger's Arch., 1906, vol. 115, p. 106. 

Brugseh: Hdb. d. Path. d. Stoffw., 1907, vol. 2, p. 570. 

Caulet: Bull. gen. de Ther., 1875. 

Caulet: Med. Zentralbl., 1875, vol. 13, p. 908. 

Freudberg: Virchow's Arch., 1891, vol. 125. 

Gudzent: Physikal. Chem. d. Harnsimre, Zentralbl. f. d. ges. Physiol, u. Path. 

d. Stoffw., 1910, No. 8. 
Henderson: Erg. d. Physiol., 1909, p. 254. 
Jawein: Ztschr. f. klin. Med, 1893, vol. 22. 
Kraus: Ztschr. f. Heilk., 1889, vol. 10. 

Loewi: v. Noorden's Hdb. d. Path. d. Stoffw., 1907, vol. 2, p. 673. 
Loewy, A.: Dubois' Arch., 1903, vol. 378. 
Magnus-Levy: Arch. f. exp. Path. u. Pharm., 1899, vol. 42. 
Meyer, H.: Arch. f. exp. Path. u. Pharm., 1883, vol. 17, p. 304. 
Minkowski: Mitt. a. d. Med. Klin, zu Konigsberg, 1888. 
v. Xoorden: Sammlung klin. Abh. u. Therap. u. Path., 1909, Nos. 7 and 8. 
Pawlow: Die Arbeit d. Verdauungsdriisen, Wiesbaden, 1898, pp. 192, 193. 
Raiinond: Ann. univ. d. med. e chir., 1884, vol. 299. 
Robertson, Br.: Jour, of Biol. Chem., vol. 6, p. 313. 
Rubner u. Rost: Arb. d. Kais. Gesundheitsamtes, 1902, vol. 19. 
Schlesinger u. Gerhardt: Arch. f. exp. Path. u. Pharm., 1899, vol. 42. 
Stadelmann: Ueber d. einfl. d. Alkalien a. d. Stoffw., Stuttgart, 1890. 
Strauss, J.: Ztschr. f. klin. Med., 1897, vol. 31. 
Szili: Pniiger's Arch., 1906, vol. 115, p. 82. 

ACIDS AND ACID SALTS 

The administration of acids may affect the gastric and intestinal 
digestion and in this way influence the metabolism (for details see 
Pharmacology of the Digestion, p. 165). During and after their 
absorption they neutralize the alkalies of the blood and of the tissues, 
and thus diminish their normal content of alkaline carbonates and 
albuminates in so far as ammonia by its vicarious action does not pre- 
vent this. A priori it is probable that the metabolic processes will be 
affected by such diminution of the alkalinity of the tissues, and that 
this is so is indicated by the manner in which autolysis is influenced 
by diminished alkalinity. Post-mortem autolysis of the organs, which 
appears to resemble closely the catabolic processes of life, is markedly 
influenced by the reaction of the surrounding medium, alkalinity, 
corresponding about to that of normal serum, strongly inhibiting it 
and, on the other hand, a slight acidity markedly accelerating it 
(Hedin u. Roivland, Wiener, Loeb u. Bar). 

In accordance with this, an increased destruction of proteids would 
be expected to result from the administration of acids, and, as a 
matter of fact, this effect has been observed in men who had taken 
inorganic acids in small amounts, for they excreted not only more 
alkalies and ammonia but also more sulphuric and phosphoric acids 



394 PHARMACOLOGY OF THE METABOLISM 

than normally (A. Keller, Dunlop). In severe acid intoxication (in 
rabbits) the production of heat is diminished and there is a lessened 
formation of carbonic acid and a diminished consumption of oxygen 
(Chvostek) . 

From these results and from what has been said previously it 
might be concluded that the proteid metabolism — i.e., its decom- 
position and cleavage — is retarded by the alkaline carbonates of the 
blood, while oxidative processes, such as the combustion of the fats 
and carbohydrates, are accelerated, and that, on the other hand, a 
diminution of the alkalinity of the blood by either exogenous or 
endogenous acids has the opposite effect. Such endogenous acidifica- 
tion, due chiefly to the formation of lactic acid, always occurs when 
the tissues are very inadequately supplied with oxygen, either on 
account of an insufficient transportation of the oxygen by the blood 
or on account of chemical inhibition of the oxidases of the tissues. 
Such disturbances will necessarily also influence metabolism in a cor- 
responding fashion, and in extreme cases will cause on the one hand 
increased destruction of the tissues and on the other fatty degenera- 
tion (A. Frankel, M. Fisher). 

Besides producing an alteration of the metabolism, the neutraliza- 
tion of the alkaline carbonates of the blood which occurs in extreme 
acid intoxication has an extremely harmful effect on all nervous 
organs, the vasomotor centres, the respiratory centre, and the motor 
ganglia of the heart being depressed or paralyzed. Under such con- 
ditions the intravenous injection of sodium carbonate may, even at 
the last moment, have a life-saving effect. 

Locally, concentrated acids produce a caustic and destructive 
effect on the tissues, while dilute acids cause slight irritation or 
stimulation or produce an astringent action and may be used thera- 
peutically for such effects. Those acids which, on account of their 
lipoid solubility, readily penetrate the skin, such as acetic and formic 
acids, are especially useful as skin irritants. Sulphuric acid and 
others may be used in the form of baths for similar purposes. 

Carbon Dioxide as a Stimulant to the Nervous System. — 
Among the acids, carbonic acid occupies a peculiar position. In so 
far as it reacts with free alkalies or with those combined with the 
weaker acids (albuminates) it acts as an acid. In addition it acts 
as neutral C0 2 which is always present in the tissues and in the 
blood, in which form it produces stimulating and depressing effects 
just as do other neutral substances which are soluble in water and 
lipoids, — i.e., the substances belonging to the group of ether and 
alcohol. The normal C0 2 tension of the tissues, which amounts to 
about 6 per cent, of an atmosphere, is of decisive significance for the 
maintenance of the normal excitability of the tissue cells and, as a 
matter of fact, is an absolutely necessary condition for its main- 
tenance. If as a result of too extreme ventilation of the lungs the 



THYROID SUBSTANCES 395 

carbon dioxide tension falls markedly, acapnia results and the nervous 
system loses its excitability, and collapse and shock develop (Y. 

Henderson). 

A. Mosso at one time attributed the phenomena of mountain sickness to 
such a deficiency of carbon dioxide, but did so incorrectly, as has been shown 
by both older and newer investigations {Zuntz, Loewi, Miller u. Caspari, Boycott 
and Ealdane). 

If, on the other hand, as a result of relatively or absolutely in- 
sufficient elimination by the lungs, the carbon dioxide content of the 
blood is increased beyond the normal, restlessness and excitation 
of the respiratory and vasomotor centres develop, while, if the increase 
be great enough, deep narcosis is caused. 

BIBLIOGRAPHY 

Boycott and Haldane: Jour, of Physiol., 1908, vol. 37, p. 355. 

Chvostek: Zentralbl f. inn. Med., 1893, vol. 14. 

Dunlop: Journ. of Phys., 1896, vol. 20. 

Fischer, M.: Das Odem. German transl. by Schorr u. Ostwald, 1910. 

Frankel, A.: Virchow's Arch., 1870, vol. 67. 

Eedin and Rowland: Ztschr. f. phys. Chem., 1901, vol. 32. 

Henderson, Yandell: Am. Journ. of Physiol., 1907, vol. 21; 1909, vols. 23 and 

24; 1910, vols. 25, 26, and 27. 
Keller, A.: Jahrb. f. Kinderheilk., 1897. 

Loeb u. Bar: Arch. f. exp. Path. u. Pharm., 1904, vol. 51. 
Wiener: Zentralbl. f. Phys., 1905, vol. 19. 
Zuntz, Loewy, Miiller u. Caspari: Das Hohenklima, Berlin, 1906. 

THYROID SUBSTANCES 
Iodothyrin, or thyroiodin, an iodine-containing substance, was 
first prepared from the thyroid glands by Baumann in 1896. It is 
obtained from a proteid containing iodine, thyroglobulin, by the 
action of heat and hydrochloric acid. In all probability this iodine- 
globulin is a secretion of the thyroid glands which enters the blood 
and exerts an important influence on the normal growth and death 
of the cells of all the organs of the body. It is for our present purpose 
of little importance whether this internal secretion or hormone pro- 
duces this " life-stimulating " action directly by a catalytic accelera- 
tion of chemical reactions * or indirectly by destroying an inhibiting 
substance. Thus far there is no evidence which forces the acceptance 
of this latter assumption, the " detoxication " hypothesis. f 

* Recently L. B. Stookey and Vera Gardner have reported that the 
autolysis <>f organs obtained from dogs thyroidectomized 5 to 10 days earlier 
proceeds more slowly than that of the organs obtained from normal animals. 
They also state that the oxidizing power of such organs, estimated by the 
oxidation of indol added to an emulsion of the organs, is weaker than that 
of emulsions of the normal liver, spleen, and kidney. Moreover, both the 
autolysis and the oxidizing power can be distinctly increased if normal dogs 
be treated for a lonjr time previously with KI, probably as a result of an 
Increased function of the thyroid glands (see the section dealing with iodine, 
p. 898). 

t For the influence of the thyroid glands or iodothyrin on the functions of 
the heart and vessels sec >■. Ci/on, Die Gefassdrtisen, Berlin, 1910, and Biedl, 
Die innere Sekretion. Wien, 1910. 



396 PHARMACOLOGY OF THE METABOLISM 

In Hypothyroidism. — If the thyroids be absent, as in thy- 
reopriva, cachexia strumipriva, or myxoedema, or if they be de- 
generated, as in endemic cretinism, the formation of the blood and 
the general growth are retarded and more or less complete myxoedema 
develops. Under such conditions the transformation of energy and 
the tissue change may be diminished to as little as % of the normal 
(Magnus-Levy). If, however, iodothyrin be administered to such in- 
dividuals, the transformation of energy and the metabolism both 
rise to, and in fact at times above, normal levels, and those cases in 
which development had ceased or in which atrophy has occurred 
regain the capacity of active growth and regeneration. As a result 
of such observations, of similar significance whether made on animals 
or on human beings, there can be no doubt that iodothyrin possesses 
the property of truly stimulating metabolism, — i.e., of stimulating 
both the anabolism and catabolism of the cell protoplasm, — and this 
stimulation apparently affects all types of cells, including the cells 
of the nervous system. The successful treatment of infantile creti- 
nism and of myxoedema by thyroid preparations is one of the most 
brilliant therapeutic achievements which have been rendered possible 
as the result of experimentation. 

Parathyroids. — Cachexia strumipriva, following the extirpation of goitrous 
thyroids, is complicated by tetany only in case the parathyroids have also been 
removed or if they have been so injured during the operation that they de- 
generate in their entirety. In this serious condition the administration of 
thyroid glands is of no avail, nor does any benefit result from administering 
parathyroid tissue internally, subcutaneously, or intravenously (Pineles). The 
parathyroids appear to be capable of performing their functions only when 
undisturbed in their own proper situation. Their function is probably that 
of rendering harmless certain unknown metabolic products. 

In normal animals and human beings, the administration of 
iodothyrin causes a similar stimulation of the metabolism, although 
naturally not to the same extent as in those cases where the function 
of the thyroid was previously entirely lacking or very insufficient. 
In many cases the normal optimal total transformation of energy can- 
not be augmented, but in others by continuous administration of 
iodothyrin for 2 to 3 weeks it can be increased about 2.5 per cent. 
Regularly and from the start the excretion of nitrogen is increased 
by the administration of iodothyrin, as a result of a more active 
decomposition of proteid material. Consequently the nitrogen bal- 
ance becomes negative and a loss of weight results (for lit. see 
Magnus-Levy) . 

In Obesity. — The augmentation of oxidation by thyroiodin has 
been observed especially often and in high degree in obese individuals, 
in whom it is not seldom accompanied by marked loss of fat. This, 
however, by no means holds good for all obese patients, and especially 
not for those in whom there is no pathological disturbance of meta- 
bolism but who have become fat essentially as a result of overeating. 



THYROID SUBSTANCES 397 

It appears that this increase of fat combustion occurs especially in 
constitutionally obese individuals who, in spite of scanty diet and 
exercise, are unable to burn up their fat. One is tempted to assume 
that in these cases the abnormal metabolism is due to a partial in- 
sufficiency of the thyroid function or that of other glands whose 
functions are of a similar nature. If this be so, the success of the 
treatment with thyroid glands explains itself. 

The exaggerated production and accumulation of fat, when the thyroid is 
insufficient or absent, appears to be due not only to the general retardation of 
oxidative processes but more particularly to the facilitation of the transforma- 
tion — i.e., the reduction — of the carbohydrates to fats, which results from 
this inadequacy of these glands. Certain clinical observations render it probable 
that the functionally active thyroid moderates or inhibits this normal trans- 
formation of the carbohydrates to fats, for not infrequently, especially in obese 
patients who are predisposed to diabetes, the administration of thyroid pre- 
parations causes glycosuria (v. Noorden). 

Symptoms of Iodothyrin Poisoning. — A number of different dis- 
turbances — rush of blood to the head, palpitation and acceleration of 
the heart, dyspnoea, sleeplessness, tremor, thirst, subjective feelings 
of heat, excessive sweating, swelling of the neck, and exophthalmos — 
have been observed to follow immoderate or careless administration of 
iodothyrin to susceptible individuals. These are all symptoms which 
are characteristic of the picture of Graves's or Basedow's disease. 
This similarity in the symptoms of the poisoning with iodothyrin to 
the symptoms of this disease is not only a superficial one but is one 
based on the similar nature of the two conditions. Almost conclusive 
proof of this essential similarity has been furnished, on the one hand, 
by the cures which are obtained in Graves's disease by the surgical 
removal of a portion of the hyperactive thyroid gland, and, on the 
other, in the almost certain demonstration of an increased amount of 
iodothyrin in the blood of patients with this disease (Beid Hunt). 

This author has discovered in the varying resistance of mice toward the 
highly toxic acetonitrile, CH 3 CN, an exceedingly delicate test for iodothyrin. 
Feeding of minimal doses (1/10 mg.) of dried thyroids increases this resistance 
200 per cent, or more. Other organic substances, including normal blood, 
possess this power not at all or only to a minimal extent, but the blood of 
patients with Graves's disease does possess it. 

These undesirable and at times dangerous effects of the thera- 
peutic administration of thyroid, particularly its power of increasing 
the decomposition of proteids, constitute a limitation for its employ- 
ment which should not be disregarded. For therapeutic employ- 
ment, as a rule, dried thyroid substances from calves or the powdered 
dried extract, or thyroiodin mixed with sugar (1.0 gm. = 1.0 gm. 
dried thyroid), are employed. 

BIBLIOGRAPHY 

Biedl: Die innere Sekretion, Wien, 1010. 
v. (yon: Die CJefiissdnisen, Berlin, 1910. 
Hunt, Reid: Journ. Am. Med. Assoc, 1907. 



398 PHARMACOLOGY OF THE METABOLISM 

Magnus-Levy : v. Noorden's Hdb. d. Path. d. Stoffw., 1907, vol. 2. 

Magnus-Levy: Ztschr. f. klin. Med., 1897, vol. 33. 

v. Noorden: Die Zuckerkrankheit, Berlin, 1907, p. 54. 

v. Noorden's Handb. d. Path. d. Stoffw., 1907, vol. 2. 

Pineles: Sitz.-Ber. d. Akad. d. Wiss.. 1908, vol. 117, p. 3. 

Stookey, L. B., and Vera Gardner: Proc. Soc. Exp. Biol. Med., 1908. 

OTHER INTERNAL SECRETIONS 

The thyroid is not the only gland exerting an influence on metab- 
olism. The hypophysis and the genital glands through their inter- 
nal secretions certainly exert an influence on metabolism and growth, 
and especially on the development of the bony skeleton. Hypoplasia 
of the genitals causes retarded and incomplete calcification of the 
epiphyses and infantilism, while hypertrophy of the hypophysis 
causes stimulation of the growth of bones, acromegalia. Both of 
these glands appear to stand in an intimate relationship with each 
other and with the thyroid, although up to the present not much is 
exactly known about this (see in this connection A. Frolich, Biedl) . 

The ancient observation that castration causes an increased ac- 
cumulation of fat has been investigated in animals by Loewy and 
Richter, who found that it caused a retardation of metabolism and 
of oxidation, which, however, according to Lilthje, does not occur in 
all cases. That these effects, when they do occur, are due to the 
absence of the internal secretion has been proven by the fact that 
the administration of ovaries or testicles can again stimulate the 
diminished metabolism, while in normal animals their administration 
produces no such effect. 

That the suprarenals also exert an influence on the general metab- 
olism is probable, for the anomalies of metabolism which are present 
in Addison's disease are best explained on this assumption. These 
observations have, however, not led to any therapeutically well- 
grounded or practically useful results for treatment. 

Still less well grounded is the employment of numerous other 
organotherapeutic preparations, such as those obtained from the 
brain, kidney, and other organs, which under various names are ad- 
vertised with unreserved laudation. 

BIBLIOGRAPHY 

Biedl: Die innere Sekretion, Wien, 1910. 

Frbhlich, A.: Wien. klin. Rundschau, 1901. 

Loewy u. Richter: Dubois' Arch. f. Physiol., 1899, Suppl. 

Liithje: Arch. f. exp. Path. u. Pharm., 1903, vols. 48 and 50. 

IODLNE AND IODINE COMPOUNDS 

While iodine must also be numbered among those substances 
especially affecting the metabolism, it does so in a peculiar and limited 
degree and only indirectly. 

Local Action. — When brought in contact with living tissues in 
concentrated solution, as in the tincture of iodine or in Lugol's solu- 



IODINE AND IODIDES 399 

tion, it produces in them substitution products and oxidizes them, 
just as it does all labile organic substances. Consequently it produces 
a destructive action in the superficial tissues and causes a more or 
less marked inflammatory reaction. That portion of the iodine which 
is not fixed at the point of application is absorbed in combination with 
proteids or lipoids or in the form of salts and can then exert its 
peculiar systemic actions. 

Systemic Actions. — These general actions are exerted essentially 
by all readily decomposed substances containing iodine, by iodine 
itself, and by the iodides, as also by iodoform or iodized fats, etc. 
Consequently the therapeutic indications for the internal administra- 
tion of all these preparations are similar, for with all of them their 
effects are due essentially to an " iodine action." This is especially 
true for the iodides. 

The iodide of potash is a very soluble and readily absorbed neu- 
tral salt and as such naturally exerts the same osmotic "salt action" 
as does sodium chloride. The peculiar actions, however, which give 
to it a special therapeutic value not possessed by the other halogen 
salts are, without doubt, to be attributed to the iodine which is set 
free from it by oxidation.* 

* In this connection reference is often made to the ion actions of iodine, 
but this cannot be taken for granted without further evidence. A solution of 
KI contains iodine ions with a negative charge, just as a solution of KC1 con- 
tains chlorine ions with a similar charge. However, as far as we know, these 
latter exert no special actions. Of them we know only that they are necessary 
for the life of the organism, and are retained by it with great tenacity, even 
when the diet contains no chlorine. 

Up to the present no one has conducted any investigations with the 
object of finding out what special physiological actions are exerted by the 
iodine anions. However, they cannot be very important, for anion actions must, 
like all ion actions, start abruptly and by their direct actions cause noticeable 
disturbances. However, large amounts of Xal may be taken by mouth or 
injected subcutaneously or intravenously without causing any noticeable direct 
disturbances, the toxic action developing, if at all, only after several days, and 
being, therefore, probably the result of secondary chemical changes {Berg, 
Sgalitzcr, Stockman, and Charteris) . Barbcra's contradictory results obtained 
by injecting a 20 per cent. Xal solution into the veins do not permit of any 
positive deductions. 

That action which we know as "iodine action" is, however, not to be 
attributed to the iodine anions but to the iodine molecules, for it is these 
which form organic combinations with various organic constituents of the 
body. It must consequently be assumed that the HI is set free from KI in the 
organism and by oxidation is transformed into I 2 and that then this produces 
the specific actions, perhaps after ionization in the form of I cations. 

If IK'l wen- as readily oxidizable, NaCl would exert CI actions. HC1 is, 
however, hardly at all affected by oxidizing agents, while HBr is readily and 
III even more readily affected by them, and consequently specific iodine and 
bromine actions may result from their administration. In accordance with the 
law of mass action, a small portion of the halogen salts is always hydrolytically 
dissociated in the body by the CCK tension which is always present. Free HI 
and lllir are very unstable and undergo oxidation even under the influence of 
atmospheric oxygen. Bine has Bhown that KI is oxidized by living protoplasm 
in the presence of C0 3 . 



400 PHARMACOLOGY OF THE METABOLISM 

The iodides and the iodized fats, in their behavior, stand in about 
the same relation to iodine as does atoxyl to arsenious acid (see 
p. 535). They can, like atoxyl, circulate about in the body as sub- 
stances which, for the time being, are indifferent or inactive and, 
wherever the necessary conditions are present, give off free iodine 
and -allow it to act, while by all means the largest part of the admin- 
istered preparation is excreted in unaltered form or, in the case of 
iodized fats, deposited in various indifferent locations. Substances 
which, like iodoform, act as undecomposed molecules will naturally 
exert actions made up of these specific actions and of iodine actions. 

Iodine possesses no power of influencing the metabolism, in the 
usual sense in which this phrase is used, for neither experiments on 
man nor on animals have demonstrated that it exerts any constant 
influence on the transformation of energy or on tissue change. Such 
action is indicated only by a series of clinical observations, such as the 
striking emaciation which occurs in some, but by no means all, in- 
dividuals who, for a long time, have taken iodine or KI internally, 
and the atrophy of certain glandular organs, especially hyperplastic 
thyroids and the mammary glands, which may also occur under similar 
conditions. This general emaciation is, however, certainly not a 
direct effect of the " iodine action." 

Effects on Mucous Membranes. — The continuous use of iodine 
preparations very often causes an active congestion with painful 
swelling and hypersecretion in the mucous membranes of the nose, 
throat, and conjunctiva and also of the pharynx and larynx, while 
more rarely the mucous membranes of the alimentary canal may be 
affected, especially if a complicating nephritis interferes with its 
excretion in the urine (v. Noorden). 

Effects on the Skin. — In a similar fashion inflammatory irritation 
of the skin occurs, with acne postules, furuncles, or purpura, all 
probably the effect of the free iodine which is formed by oxidation 
from the iodine excreted in the glands of the skin. 

Effects on Nutrition. — These inflammations of the mucous mem- 
branes, especially if they affect the stomach, can produce a marked 
disturbance of nutrition and may occasionally lead to emaciation. 
Ordinarily, however, even after the use of large amounts of KI for 
months at a time, this does not occur except in certain patients with 
goitre. 

Effects on the Thykoid. — In such individuals the administration 
of iodine in any form is followed, often after a few small doses, by the 
development of the typical clinical picture of thyroidism or Graves's 
disease, with the rapid loss of weight and strength characteristic 
thereof (Brewer, Pineles). It may consequently be concluded that 
iodine influences the metabolism only indirectly, through the thyroid 
glands, and to an appreciable degree only in case the thyroid tissue 
is hypertrophic but at the same time functionally insufficient. Such 



IODINE AND IODIDES 401 

conditions of the thyroid are present in many cases, and are due in 
all probability to a too small amount of iodine in the glandular tissue. 

It is well known that the physiological activity of the thyroid 
gland is determined by the- amount of thyroiodin present in it and 
that the poorer it is in iodine the less active it is. This has been 
proven experimentally by Oswald, Boos, and others, and in a very 
peculiar fashion by Beid Hunt and Atherton Seidell. Hoisted states 
that the lack of a sufficient amount of active iodothyrin in a thyroid 
causes the hypertrophic formation of glandular tissues which are 
poor in colloids and, therefore, chemically and functionally insufficient. 
The new-born offspring of animals deprived of their thyroids have 
markedly hypertrophied but colloid-free thyroids {Hoisted, Edmunds, 
A. Kocher, Beid Hunt), and hyperplastic human or annual thyroids 
contain little or no iodine (Oswald). On the other hand, the amounts 
of thyroiodin contained in the thyroid is increased by the admin- 
istration of KI or other iodine preparations, while the hyperplastic 
tissues poor in colloids atrophy and the goitre diminishes in size. 

From all this it can hardly be doubted that iodine changes the 
functionally weak thyroid tissue which is poor in iodine into one rich 
in iodine and physiologically active, and that in this way it causes 
the disappearance of the superfluous hyperplastic glandular tissues. 
This conception of the action of iodine enables us to understand 
the pronounced augmentation of the catabolic processes in the whole 
body which sometimes, particularly in cases of thyroidism, occurs 
under the influence of iodine medication and which may be ac- 
companied by temporary febrile manifestations. From the foregoing 
it is clear that the iodine treatment of goitre, introduced by Coindet 
in 1820, rests upon a physiological basis. 

In Scrofula. — Whether or not the benefits resulting from the 
iodine treatment of scrofulous swelling of the lymph-nodes are to be 
explained in the same fashion is uncertain, particularly as no attempt 
has been made to determine whether or not the scrofulous diathesis 
of many (but by no means all) tubercular patients is dependent on 
an insufficiency of the thyroid. It is possible that in these cases the 
favorable results are due to a direct action of iodine which accelerates 
the decomposition or destruction of the pathological tissues. It is 
also possibly of significance that tubercular tissue absorbs iodine 
more strongly than normal tissues (Loeb u. Michaud). 

In Syphilis. — The same question arises in connection with the 
symptomatic curative effects of the iodides in syphilis. There is no 
doubt that under their influence there occurs a rapid degeneration 
juicl disappearance of syphilitic lesions, aspecially those of the second 
and third stages, but a definite cure, with prevention of relapses, is 
Dot obtained by the use of the iodides. A definite etiotropic * action 
cannot be attributed to it. 

* An etiotropic action is an action directly on the specific organism 
causing a disease. 
26 



402 PHARMACOLOGY OF THE METABOLISM 

In Atheroma. — The alleged curative action of iodine in atheroma 
is quite as difficult of explanation. The functional disturbances oc- 
curring in arteriosclerosis which are due to the faulty blood flow 
through various organs — e.g., in cerebral arteriosclerosis and angina 
pectoris — are often distinctly benefited by KI if the condition is not 
too far advanced. According to Romberg, this is due to this drug's 
power of diminishing the alkalinity of the blood, which change per- 
mits of a more ready flow of blood through the atheromatous vessels 
(0. Mutter u. Inada). How this effect is brought about is not known 
(Adam). The alleged vasodilating action of KI does not exist 
(Stockman and Charteris). Thaussig's observations of a diminution 
of the hypertension of the vessels in chronic lead poisoning, which he 
explained as due to a vasodilating action, are the result of the ac- 
celerated elimination of the lead, which results from the administra- 
tion of iodides. 

The beneficial action of iodine in nervous asthma * and in neuralgias 
is altogether incomprehensible, but its beneficial effect in chronic lead 
and mercury poisoning has been understood since it was shown by 
Melsens in 1844, and later by others, that the elimination of these two 
metals is distinctly accelerated by the administration of the iodides. 

Administration. — For the various indications mentioned, the 
iodides of potassium and of sodium are administered in doses rang- 
ing from 0.1 gm. up to 20.0 gm. or more per day, or the newer organic 
iodine combinations, such as iodipin and sajodin, may be employed. 
The former is a combination of iodine with the unsaturated fatty 
acid of sesame oil, and is obtainable in two strengths, one containing 
10 per cent, and the other 25 per cent, of iodine. Sajodin is a cal- 
cium salt of a fatty acid and contains 20 per cent, of iodine. 

BIBLIOGRAPHY 

Adam: Ztschr. f. klin. Med., 1909, vol. C8. 

Barbera: Pfiiiger's Arch., 1898, vol. 68. 

Binz: Virchow's Arch., 1874, vol. 62. 

Breuer: Wien. klin. Woch., 1900, Nos. 28 and 29, here literature. 

Edmunds: Transact. Pathol. Soc. London, 1900, vol. 51, p. 221. 

Halsted, W. S.: Johns Hopkins Hosp. Rep., 1896, vol. I, p. 373. 

Hunt, Reid: Journ. of Biologic Chemistry, 1905. 

Hunt, Reid: Journ. Am. Med. Assoc, 1907. 

Hunt, Reid, and Atherton Seidall: Labor. Bull. 47, Washington, 1900. 

Kern, H.: Diss., Tubingen, 1909. 

Kocher, A.: Mitt. a. d. Grenzgeb. d. Med. u. Chir. 

Loeb u. Michaud: Biochem. Ztschr., 1907, vol. 3. 

Miiller, O., u. Inada: Deut. med. Woch., 1904. 

v. Noorden: Med. Klinik., 1908, No. 1. 

Oswald: Sammelref. Biochem. Zentralbl., 1903. 

Pineles: Wien. klin. Woch., 1910, No. 10. 

Sgalitzer: Arch, de Pharmacodyn., 1908. 

Stockman, A., and Charteris: Brit. Med. Journ., 1901, here literature. 

Stockman and Charteris: Brit. Med. Journ., 1901, Nov. 

Thaussig: Wien. med. Woch., 1902, No. 29. 

* See page 347. 



QUININE 403 

QUININE 

As other physiological and therapeutic actions of quinine will be 
discussed elsewhere (pp. 470 and 527), our attention will here be di- 
rected only to the direct effects of this drug on the chemical activities 
of living cells. 

The antipyretic action of calisaya bark, which has been known 
ever since its introduction in medicine, and the improvement in the 
general state of nutrition of run-down individuals which results from 
its administration, early indicated the propriety of investigating its 
effects on metabolic phenomena. Even to-day quinine enjoys a reputa- 
tion as a tonic or means of improving the general health. 

The main facts concerning the actions of quinine on metabolism 
may be stated briefly as follows. Quinine retards all the vital pro- 
cesses of the cells, inhibiting both anabolic and catabolic reactions. In 
this fashion, even small doses of quinine possess the power of sparing 
the tissues of the body, but when its effects are produced in the highest 
degree it acts as a general destroyer of life, and causes a complete 
cessation of the production of energy. On what elementary action 
this depends is entirely unknown. We know only that it may be 
observed in almost all living organisms, in the lower and higher 
plants, in protozoa, and higher up in the scale of life. Probably it is 
due to an action on the enzymes, which are, as it were, the chemical 
tools of the cells, for pure enzyme actions are weakened or entirely 
inhibited by quinine (Laqtieur), which possesses the power of in- 
hibiting oxidative and synthetic reactions, such as the formation 
of acid in the blood, the guaiac reaction, the formation of hip- 
puric acid in the kidney, the phosphorescence of phosphorescent 
bacteria, and also the hydrolytic and catabolic reactions in living or 
surviving organs. 

Consequently, in neither the lower nor the higher organisms does 
quinine cause a stimulation of vital processes or of regeneration or 
stimulation of growth, such as is observed under the influence of 
thyroiodin. 

Even the apparent stimulation of muscular power, which is observed 
at the start of the quinine action, is not the result of any true increase in 
the production of energy^ although, according to Santesson, there is at first 
;ui augmentation of muscular work, which, however, is quickly followed by 
a correspondingly more rapid exhaustion. This may be attributed to an 
inhibition of anabolic processes, as is done in connection with the analogous 
action of alcohol [Frohlich, Lee). Particularly for quinine this appears to 
be the correct explanation. 

All exact observations agree in indicating tliat the proteid metab- 
olism, is diminished, hi) (/niniiir, the nitrogen balance showing that 
less nitrogenous material is decomposed when quinine is given than 
is normally the case. This is true in health and in fever, when food is 
taken or when the patient is fasting (Loewi). 

As Wider normal conditions the central heat-regulating mechan- 
ism, which is hardly at all narcotized by quinine (on the contrary, 



404 PHARMACOLOGY OF THE METABOLISM 

it is perhaps slightly stimulated at the start), sees to it that the 
lessening of heat production is compensated for by diminished heat 
loss (Gottlieb) or by an increased oxidation of non-nitrogenous sub- 
stances, under normal conditions, closes, which are not too large, do 
not alter the total transformation of energy as measured by con- 
sumption of oxygen and excretion of carbon dioxide, nor, as a rule, 
do they produce any alteration in the body temperature, except that 
occasionally in nervous or excitable individuals such doses may at 
first cause a slight rise in temperature (Fr. Miiller). 

In Fever. — If, however, the heart-regulating mechanism is in- 
adequate and readily fatigued, as is the case in infectious fever, the 
general inhibitory effect of quinine on the chemical processes in the 
body causes an alteration of the respiratory exchange of gases, due to 
a diminished oxidation of all substances, both nitrogenous and non- 
nitrogenous, and the total production of heat is diminished (see 
Antipyretics, p. 470). The direct effect of quinine on the central 
nervous system, which may cause motor restlessness and increase of 
the respiratory volume, and its effects on the circulation, namely, ac- 
celeration of the heart-rate, may mask this fundamental action on 
metabolism. 

From the foregoing it may be seen that a therapeutic invigorating 
effect on the metabolism, leading to an improvement in the nutrition, 
is not to be expected from quinine, for it certainly does not favor 
the formation of new cell material and probably inhibits it. How- 
ever, it may exert a conservative sparing action, particularly in such 
conditions as thyroidism, infectious fever, etc., in which the catabolic 
processes are abnormally increased as a result of pathological stimuli 
and in which there is a rapid loss in weight and strength. Quinine 
may be said to retard the processes not only of life but also 
of dying. 

BIBLIOGRAPHY 

Frohlich: Ztschr. f. allgem. Physiol., 1905, vol. 5. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1890, vol. 26. 

Laqueur: Arch. f. exp. Path. u. Pharm., 1906, vol. 55, here literature. 

Lee, F. S.: Am. Journ. of Physiol., 1907, vol. 20, p. 170. 

Loewi : Hdb. d. Path. d. Stoft'w., 1907, vol. 2, p. 792. 

Miiller, Fr.: Arch. f. klin. Med., 1893, vol. 51. 

SUBSTANCES INHIBITING OXIDATION ("Arsenic Group"). 

Lack of Oxygen. — Augmentation of the normal — apparently 
optimal — oxidation of the blood produces no effects on the metabolism, 
bat diminution thereof produces very important effects, which, in 
their character and intensity, vary greatly with the more or less in- 
sufficient supply of oxygen. 

A slight diminution of the oxygen tension in the atmospheric air, 
such as is met with in altitudes of about 1000 metres above the sea. 
level, causes an increased production of new red cells and probably 
also of other tissues, particularly of the muscles, for with the same 



WATER AND SALT ACTIONS 405 

intake of food much more nitrogen is retained than corresponds to 
the newly formed haemoglobin {Jaquet, Jaquet u. Stahelin). v. 
Wendt's careful experiments on himself at heights of between 3000 
and 4500 M. showed that, in addition to a marked retention of nitro- 
gen, there is a retention of sulphur and iron and also increased as- 
similation of phosphorus. The respiratory exchange of gases is also 
increased under these conditions, a fact probably of much importance 
in connection with the therapeutic effects of the high altitudes. 

Very insufficient oxygen supply, on the other hand, such as 
results from severe hemorrhages, anaemias, and dyspnoea, leads to a 
marked and readily recognizable disintegration and degeneration of 
tissues, with fatty degeneration and abnormal production of acids, 
and to a retardation of synthetic processes, such as that of hippuric 
acid in the kidney, etc., and finally to paralysis of all functions. 

Just as a moderate insufficiency in the oxygen supply causes a 
favorable stimulation of the metabolism and the retention of nutri- 
tive material, and as a more pronounced deficiency causes an increased 
destruction of tissues, a number of chemical agents produce the 
same results. It, therefore, is not improbable that their action in the 
last instance depends on their power of preventing the protoplasm 
from utilizing oxygen (Loewi). The more important of these sub- 
stances are : 

(a) Phosphorus. 

(b) Arsenic and antimony and their compounds. 

(c) Iron and mercury. 

BIBLIOGRAPHY 

Frankel: Virchow's Arch., 187G, vol. 07. 

Jaquet: Proftramm Basel, 1904. 

Jaquet u. Stahelin: Arch. f. exp. Path. u. Pliarm., 1901, vol. 46. 

Loewi: Hdb. d. Path. d. Stoffw., 1907, vol. 2, p. 693. 

Prausnitz: Sitz.-Ber. Ges. Morph. u. Physiol., Miinchen, 1890. 

v. Wendt: Arch. Physiol. Inst. d. Univ. Helsingfors, 1910, p. 151. 

PHOSPHORUS 

It is only the chemically active yellow phosphorus which possesses 
a pharmacological action, and it appears that only phosphorus itself 
and not its combinations produce these effects, for there are no known 
compounds containing it which produce the same or even similar 
actions ( Schuchardt) unless nascent phosphorus is set free from them 
(Santesson) . 

Phosphorus is very slightly soluble in water, but fairly so in 
many organic solvents and in Eats. It is slowly absorbed from the 
alimentary canal, and its characteristic effeels develop only slowly 
and gradually. In the body it appears to be hardly oxidized a1 all 
extra-eellnlarly, for it remains unaltered when suspended for days 



406 



PHARMACOLOGY OF THE METABOLISM 



in arterial blood (//. Meyer), although outside of the body it is very 
readily oxidized when exposed to air. 

Effects on General Metabolism. — When taken in very small 
amounts (%-T mg. per diem in man) phosphorus stimulates metabo- 
lism, causing an increased growth and new formation of tissues. 
AYhile exact metabolism experiments on children or young animals 
have never been made, this may be concluded from the favorable 
effects on the general state of nutrition observed by clinicians and 
from the unusual increase in the weight of rhachitic children to whom 
phosphorus has been given (Kassowitz, Hagenbach, Neumann). On 
the other hand, w r e possess a more exact knowledge of its effects on 
the blood and on the bony tissues. 

On Blood. — Among the first effects of the action of phosphorus 
in man is an increase in the number cf red blood-cells (Gowers, 
Thaussig), and even after large toxic doses the production of the 




Normal. 

Figs. 44, 45. 




After phosphc 
-Heads of calves' femur (from Wegner). 



red cells appears to be increased beyond the normal, for in severely 
poisoned mammals their number is not, as a rule, diminished, al- 
though the markedly increased production of bile pigments indi- 
cates an increased destruction of the red cells * (Stradelmann) . 

On Bone. — Phosphorus influences the formation of bone very 
markedly. In young animals the growing portion of the epiphyses 
forms a compact bone instead of a spongy substance and the osseous 
tissue hypertrophies at the expense of the medulla (Wegner) (Figs. 
44 and 45). These effects appear to be similar to those which Schiff, 
after dividing the nerves of the leg, observed in the bones of the leg 
and foot of young animals as the result of the continuous congestion 
and inflammatory irritation from a wound. Phosphorus thus un- 
doubtedly stimulates the growth of bone, or, otherwise expressed, 
causes the anabolic processes in the metabolism of bony tissues to 

* In the chicken, while the destruction of these cells is at first so great 
as to more than keep pace with their new formation and their number is 
markedly diminished, the rapid return to normal numbers shows that the new 
formation of the red cells takes place very rapidly {Gowers, Thaussig, J. Vogel). 



PHOSPHORUS 407 

preponderate over the catabolic ones. By chemical analysis Kochmann 
has demonstrated a relative increase in the calcium of the bones 
under the influence of chronic phosphorus poisoning. This increase 
amounts to a change of from 21 per cent, to 25 per cent, of the 
dried residue. 

Toxicology. — The harmful effects of poisonous doses of phosphorus 
manifests itself to a much greater degree in the metabolism of the 
other organs. Morphologically it may be readily recognized ma- 
croscopically in the liver, heart, and kidneys, and to some extent 
in the diaphragm and the other muscles, all of which show fatty 
degeneration to a greater or less extent. In the liver and in the heart, 
this fatty degeneration is due to the fact that fat from other tissues 
is deposited in them (Loewi), but in the kidneys it appears to be due 
to the fact that the fat and lecithin normally present in them, but, 
as it were, hidden or combined, is set free and becomes visible (Buboiv, 
Mans f eld). As the capillary epithelial cells also are the seat of 
fatty degeneration, small hemorrhages readily occur. By chemical 
analytical methods it may be shown that phosphorus causes a greatly 
increased destruction of the tissues, with marked disturbance of the 
synthetic, oxidative, and cleavage reactions. 

The consumption of oxygen and the formation of C0 2 is lessened. 
Less fat and correspondingly more carbohydrates and proteids are 
combusted, which latter, however, are only in part completely broken 
down, so that considerable quantities of intermediary metabolic pro- 
ducts (amino acids, peptones, lactic acid, and many others) are 
present in the blood. In agreement with this, there is a marked 
augmentation of the autolytic decomposition of proteid in the livers 
of animals poisoned by phosphorus, as compared with normal organs 
(Jacoby). Moreover, the addition of phosphorus to the perfused 
blood strongly inhibits the synthesis of hippuric acid in the isolated 
kidney (Hauser). 

As has already been mentioned, these disturbances of metabolism 
agree in many particulars with those resulting from the lack of oxy- 
gen, and it is consequently not at all improbable that phosphorus 
renders the body cells less capable of utilizing oxygen in the normal 
fashion. 

In its effects on function, phosphorus poisoning manifests itself 
by a progressive diminution in the functional power of all the organs. 
The cells of the brain become incapable of performing their normal 
functions, and the poisoned individual falls into a state of apathy 
and unconsciousness, — sometimes, however, into a state of delirium. 
The movements of the body become sluggish and feeble and the heart 
and the vasomotor apparatus are paralyzed. If large amounts of 
phosphorus reach the blood relatively rapidly, a direct paralysis of 
the heart may precede all other symptoms (IT. Meyer). 



408 PHARMACOLOGY OF THE METABOLISM 

The only efficacious treatment of phosphorus poisoning is the 
removal of the poison from the stomach or the attempt to render it 
harmless by securing its oxidation in the alimentary canal. Copper 
sulphate is the substance best adapted for this purpose, for not only 
does it cause emesis, but by its reduction the phosphorus is oxidized 
to phosphoric acid, and at the same time any phosphorus still un- 
changed combines with the reduced copper, forming an insoluble 
copper phosphide. Permanganate of potash also energetically oxi- 
dizes phosphorus, but ozonized turpentine which is recommended as 
an antidote is of doubtful value [and certainly cannot act on the phos- 
phorus once it is absorbed. — Tr.]. 

Therapeutic Uses. — After phosphorus was discovered to be an 
important constituent of the brain and nerves, it was for a long time 
used with alleged great benefit in the treatment of different nervous 
disturbances. In view of the similar employment of arsenic, which, 
as will be seen below, acts in an entirely analogous fashion, which 
employment is still considered as justifiable, these older claims of the 
value of phosphorus in such conditions should not be dismissed off- 
hand as erroneous. 

Wegner's experiments have furnished a scientifically founded jus- 
tification for the employment of phosphorus in osteomalacia and in 
rickets, as first recommended by Kassowitz. In particular, its curative 
effect in rhachitic children is not to be disputed, in which connection, 
it should be noted, that not only does formation of bone become 
normal again, but the other accompanying symptoms of rickets often 
disappear with surprising rapidity. All the same, the risks in pre- 
scribing phosphorus are not slight, for the rapidity with which it is 
absorbed from the alimentary canal and, consequently, the intensity of 
its effects, appear to be very variable and impossible to estimate. Doses 
of 1 mg. of phosphorus daily (two teaspoonfuls of phosphorus and 
cod-liver oil in the proportion 0.01: 100), as ordinarily prescribed by 
pediatrists, are almost always borne without harm, but such doses 
taken for several days have also led to a fatal poisoning (Nebelthau). 
The attempt should, therefore, be made to abandon the therapeutic 
employment of phosphorus, replacing it by arsenic. 

BIBLIOGRAPHY 
Berg: Diss., Dorpat, 18. 

Gowers, by Limbeck: Grundriss d. Path. d. Blutes, Jena, 1892. 
Hagenbacii: Zbl. f. Schweiz. Aerzte, 1884. 
Hauser: Arch. f. exp. Path. u. Pharm., 1895, vol. 36. 
Jacobv: Ztschr. f. physiol. Chemie, 1900, vol. 30. 
Kassowitz: Ztschr. f. klin. Med., 1884, vol. 7. 
Kochmann: Pfiii^er's Arch., 1907, vol. 119, p. 417. 
Loewi: v. Noorden's Handb. d. Path. d. Stoffw., 1907, vol. 2, p. 778. 
Mansfeld: Zentralbl. f. Physiol., 1907, vol. 21, p. 666. 
Mej-er, H.: Arch. f. exp. Path. u. Pharm., 1881, vol. 14. 
Nebelthau: Miinchn. med. Woch., 1901, No. 34. 
Neumann: Diss., Rostock, 1896. 
Rubow: Arch. f. exp. Path. -u. Pharm., 1905, vol. 52. 



ARSENIC 409 

Santessen u. Malmgren : Skand. Arch. f. Physiol., 1904, vol. 15, pp. 259 and 420. 

Schiff : Compt. rend. Acad, des Sciences, 1854. 

Schuchardt: Ztsehr. f. rat. Med., 1856, N. F., vol. 7. 

Stadelmann: Arch. f. exp. Path. u. Pharm., 1S87, vol. 24. 

Thaussig: Arch. f. exp. Path. u. Pharm., 1892, vol. 30. 

Vogel, J.: Arch. u. Pharmacodyn., 1902, vol. 10. 

Wegner: Virchow's Arch., vol. 55, 1872. 

ARSENIC 
All arsenical combinations which are capable of reacting chemi- 
cally are pharmacologically active, producing effects which in the last 
instance are due to the action of the anion As0 3 or As0 4 . The 
organic arsenical compounds, such as cacodylic acid, (CH 3 ) 2 As0 2 H r 
and arseniuretted hydrogen, AsH 3 , however, first produce their own 
peculiar effects, the latter, for example, being very powerfully 
hemolytic and in this fashion capable of producing fatal results. 
With the continuous administration of small quantities of such sub- 
stances these characteristic actions are hardly apparent, but as a 
result of the formation from them of As0 3 (Heffter) they gradually 
cause the typical effects of arsenic. The same holds true for atoxyl 
or sodium arsanilate {Igersheimer) . 

There is no evidence that either arsenous or arsenic acid forms any com- 
bination with any of the constituents of the protoplasm. Their solutions 
consequently, for the time being, produce no visible morphologic changes or 
functional effects in the nerves or other tissues. After a time, however, the 
poisoned cell dies and undergoes post-mortem changes. It is not known 
whether this is due to a catalytic inhibition of vitally important chemical 
reactions, or is due to a chemical reaction between arsenic and some constituent 
of the protoplasm, minimal amounts of which are necessary to the life of the 
cell. As ferments are not markedly influenced by arsenic, the catalytic effect 
does not, a priori, seem very prohable (tichafer u. Bbhm) . On the other hand, 
the possibility of a specific chemical combination between arsenic and some 
constituent of protoplasm is rendered improbable by Bertrand's statement that 
arsenic is an integral constituent of all living cells. This author found 1/200 
mg. of arsenic in the hen's egg, chiefly in the yolk. 

Ox Metabolism. — In its nature the action of arsenic on metabo- 
lism is essentially the same as that of phosphorus. In very small 
amounts it inhibits oxidation and exerts a favorable influence on 
growth and assimilation, causing a preponderance of assimilative 
processes as compared with those of dissimilation. The breeders of 
animals have long recognized this effect, and the so-called arsenic 
eaters in Steiermark look upon this as definitely established. The 
chemist, Kopp, observed that he gained 10 kilograms in weight during 
the course of two months in which he was working with arsenical 
substances (Gies). These practical experiences have been confirmed 
by exact observations on animals, in which the growth of normal 
minimis was compared with that of Ihose receiving arsenic, and by 
making exact analyses of the metabolism under the influence of 
arsenic (W< lake). In Oies's new-born rabbits of the same litter, to one 
of which arsenic bad been administered daily, there was after four 
weeks a difference in weight of 30 per cent, in favor of the animal 



410 



PHARMACOLOGY OF THE METABOLISM 



fed with arsenic, which was also distinguished from its control by a 
shining pelt and a more abundant supply of fat in the subcutaneous 
tissues and in the peritoneal cavity. The bones of the arsenic animal 
were longer and. thicker in the cortex, and the epiphyses con- 
sisted of thick, compact masses of bone such as result from the action 
of phosphorus (Fig. 46) . Similar observations have been made in pigs 
and fowls, and, furthermore, the offspring of animals treated with 
arsenic were much stronger than those of the normal controls. 

On Blood, — It is probable also that the formation of the red 
cells or the manufacture of haemoglobin (Delpeusch) is stimulated 
by arsenic, but this has not been denitely proven (Bcttmann, Stock- 
man; see also Pharmacology of the Blood, p. 435). 

Corresponding to this improvement of the assimilative processes, 
the nitrogen balance shows a retention of nitrogen, indicating in- 




Fig. 4G. — Rabbit femurs. 



creased assimilation of proteid (Weiske, Imjanitoff). Nothing de- 
finite is known of the influence exerted on the total metabolism by 
small doses of arsenic. 

It has been claimed that arsenic exerts a favorable influence on the 
development of infusoria (Sand), higher plants {Zeller, 1826), and yeasts, etc. 
(Schultze) . 

Toxic Effects. — Contrasted with the effects of small doses of 
arsenic in favoring assimilation and facilitating growth and regener- 
ation are the opposite effects of large doses of arsenic, which cause 
an increased destruction of the tissues of the body and an inhibition 
of the functions of various organs. Among these effects are injury 
and abnormal destruction of the red cells (Bettmann, Stierlin, Stock- 
man, Chart eris) and as a result of this the development of jaundice, 
while the nitrogen balance indicates an increased destruction of 
proteids (Gathgcns, Ko-ssel, Imjanitoff) and at the same time the 
respiratory exchange of gases is diminished (Chittenden). Fatty 
degeneration of the organs also ensues, lactic acid appears in the 
blood and in the urine, and the liver loses its power of forming 
glycogen (Naunijn, Luchsinger, Konikoff). 



ARSENIC 411 

Combination of Assimilative and Disintegrative Actions. — Often, 
and perhaps as a rule, both of these effects of arsenic, the stimulation 
of growth and the destruction of the tissues, occur at the same time. 
Corresponding to the momentary resistance and vital powers of the 
different cells, and even more to the varying distribution of the 
poison in the different parts of the body, in one place the favorable 
building-up action preponderates, in another the destructive, while 
in still other situations no appreciable effect occurs.* 

In chronic arsenical poisoning in the normal body those cells are 
especially affected which perform the larger portion of and the most 
complicated of the chemical reactions, particularly the cells of the 
liver, the kidney, the capillaries, and the blood. Certain pathological 
new growths, such as malignant lymphoma, syphilitic gummata, etc., 
appear to be especially susceptible to the dissimilative actions of 
arsenic. It is thus possible to produce such effects in many patho- 
logical growths without seriously or permanently injuring the patient 
himself. 

Acute Poisoning. — Up to the present it is not possible to ex- 
plain satisfactorily the therapeutic effects of this drug by our knowl- 
edge of the direct functional disturbances occurring in experimental 
acute arsenical poisoning. In poisoning of this type, frequently but 
not always, the symptomatic picture is dominated by two groups of 
symptoms which develop alongside of each other, one group being 
the result of depression, and, in more severe cases, of very acute 
paralysis of the central nervous system, while the other is due to 
the severe gastro-intestinal lesions. The former cause extreme las- 
situde, unconsciousness, and coma and failure of the respiration and 
circulation from paralysis of the respiratory and vasomotor centres, 
while the lesions in the alimentary canal, which also develop after 
subcutaneous or intravenous administration, cause violent pains, 
vomiting, and choleraic diarrhoea. 

There appears to be a close connection between the gastro-intestinal 
disturbances and the disturbance of the circulation which develops 
at the same time and manifests itself by a pronounced fall in the 
arterial blood-pressure and a small, weak pulse. Experimental an- 
alysis of the circulatory failure has shown that, in addition to a weak- 
ening of the heart muscle, there is a diminution of the excitability 
of the vasomotor centres, and that finally the intestinal vessels no 
longer react to electric stimulation of the splanchnic nerves in the 
periphery. The contractile elements of the capillaries of the portal 
syslon arc completely paralyzed, so that the blood accumulates and 
stagnates in them and their veins (Pistorius, Heubner). As a result 
of this capillary paralysis, there is a profuse transudation of serous 

* Tlio difference in effect ib especially well evidenced in plants, those con- 

ta i niriLT chlorophyll liein^ especially susceptible to arsenic: of those containing 

none, the yeast fundus and many bacteria are very insusceptible, while the 
mycoderma oidium is entirely immune. 



412 PHARMACOLOGY OF THE METABOLISM 

fluid into the intestines, whose epithelium, being herp and there fattily 
degenerated, is raised up, and with the masses of the exudate may 
form a pseudo-membrane. A profuse watery diarrhoea results, the 
stools containing shreds of mucous membrane and at times blood. 

As the mucous membrane of the intestine is directly injured as a result 
of the stasis, and probably in part also by the arsenic excreted through it, it is 
not able to resist the attacks of the bacteria to which it is constantly exposed, 
and parts of it succumb to a rapid destruction, so that ulcers may be formed 
(toxic autolysis). Necroses therefore are likely to be more extensive and 
severe in the large intestine than in the small intestine, which contains 
relatively few bacteria (Cloctta). 

Among the less direct effects are pronounced anemia of all the 
other organs, anuria, asphyxia of the central nervous system, con- 
vulsions, and paralysis. 

The central paralysis caused by arsenic is, however, not due to this 
interference with its blood supply, but to a direct toxic action of the drug. 
This is shown by the results of experiments on the frog, whose central nervous 
system is rapidly paralyzed from below upward when poisoned by arsenic, 
although it can support for hours an anaemia — for example, one caused by a 
standstill of the heart or by replacing the blood with normal NaCl solution. 

The blood and lymph capillaries of the splanchnic system are more 
susceptible to arsenical poisoning than those in any other portion 
of the body, and in very acute poisonings are almost the only ones 
visibly affected. 

In chronic poisoning, however, or when the drug is used medicin- 
ally for a considerable period of time, capillary paralysis and de- 
generation also occur, and often in fact chiefly in other mucous mem- 
branes and in the skin. This accounts for the conjunctivitis with 
oedema of the lids and for the angina, rhinitis, etc., and for the de- 
velopment of exanthemata resembling measles or scarlatina, as well 
as of herpes zoster, all of which are not infrequently observed under 
these conditions. Finally, arsenical melanosis, a brown pigmentation 
of the skin, resulting from chronic inflammation, may develop and 
last for months or years. The lesions of the peripheral nerves, poly- 
neuritis, which may develop in chronic arsenical poisoning, are 
probably also to be attributed to a primary toxic action on the 
capillaries of the nerves. 

Therapeutic Actions. — We have no exact knowledge of the extent 
to which curative effects of arsenic are due to such actions on the 
capillaries in the skin, the nervous system, and elsewhere. It is 
possible that this is of moment in the healing of the lesions of psoriasis. 
For the present, however, we have no explanation for the clinically 
well-established value of arsenic as a means of relieving neuralgias 
and many neuroses, such as chorea and asthma nervosa. 

On the other hand, the already mentioned primary action of 
As0 3 on metabolism, which, according to the individual susceptibility 



WATER AND SALT ACTIONS 413 

or accessibility of the cells of the different organs, results in an ac- 
celeration of the growth or death and destruction of the cells, may 
"be considered as a theoretical justication for prescribing arsenic in 
those cases in which the indication is either to improve the nutrition 
and growth of organs which are too feebly developed or to cause 
an absorption or destruction of pathological new growths or the 
destructions of parasities. Such are a poor state of general nutrition, 
cachexia, chlorosis, pathological disturbances of the growth of bones, 
such as ricketts or osteomalacia, in which last arsenic should be sub- 
stituted for phosphorus, the action of which it is so much more difficult 
to estimate. Malignant lymphoma, pseudoleukemia, syphilis, and some 
parasitic diseases are examples of the type of case in which the 
destructive effects are desired. 

The ordinary doses range between 0.5 and 5.0 mg. of arsenic 
trioxide (arsenious acid), which may be administered in different 
preparations or in mineral waters containing arsenic. 

In conclusion, the use of arsenic pastes to cause a local destruction 
or death of tissues should be mentioned. Their use is now almost 
entirely limited to their employment in dentistry for the purpose of 
killing the nerves in the roots of teeth, but formerly they were widely 
used as a means of destroying superficial epitheliomata. 

The organic arsenical compounds have been found to be 
especially adapted to produce an etiotropic effect on parasites with 
the greatest degree of certainty and without essentially injuring the 
patient. Among such preparations atoxyl and salvarsan (see p. 535 ff.) 
are especially to be mentioned. 

Excretion and Fat in the Body. — Arsenious acid is excreted from 
the body but slowly, and it would appear that it is never completely 
excreted. The lacteal glands 1 are among the organs through which 
this excretion takes place, but after administration by mouth a con- 
siderable amount is excreted in the faeces, a smaller part, 4 to 14 
per cent., appearing in the urine, while a very important remainder, 
varying from 20 to 80 per cent., is never excreted in any recognizable 
manner (Ilausmann, Ileffter). After subcutaneous injection, the 
same holds good, except that now the larger portion, from 10 to 19 
per cent., is excreted in the urine, and the smaller part, from 3 to 4 
per cent., in the feces. A small part of the arsenic is absorbed by 
and retained in the hairs, and leaves the body in hairs and other 
epidermoid structures as they are cast off. Whether arsenic remains 
permanently in the body and in what form or place (perhaps in the 
bones .' I is not known. 

Tolerance. — If at first the arsenic be carefully administered in 
small doses, tolerance increases to such an extent that after a time 
• loses may be borne without injury which would otherwise be certain 
to cause illness, and perhaps even as much as 3 or 4 times the usual 
Lethal dose may be taken without harm. This has been observed 



414 PHARMACOLOGY OF THE METABOLISM 

in the arsenic eaters of the Steiermark and has been confirmed by ex- 
periments on animals (Hausmann) . [Clinical experience also indi- 
cates that a marked degree of tolerance is readily established. — Tr.] 
Under these conditions the organism apparently retains larger 
amounts of the drug and possibly acquires a greater ability to form 
nontoxic organic combinations of arsenic. Cloetta, however, claims 
that the tolerance is due to the fact that the absorption of arsenic 
from the alimentary canal decreases, the mucous membrane of the 
intestines becoming resistant and impermeable to it. Whether at the 
same time a general habituation of the cells to the specific action of 
arsenic also takes place has not been sufficiently investigated. With 
yeast-cells this appears to be the case, but in animals it is very 
doubtful. Hausmann found only that the mucous membranes of 
dogs which were accustomed to take arsenic were distinctly more 
resistant to the caustic action of As 2 3 than were those of normal 
animals. Cloetta' s dogs, which had become habituated to arsenic, 
died a few hours after the subcutaneous injection of only one- 
sixtieth of the dose which for months past had been taken by mouth 
without injury. 

BIBLIOGRAPHY 

Bettmann: 1897. Cited by Stockman and Charteris. 

Chittenden: Cited by JMaly, 1887, p. 17. 

Cloetta: Arch. f. exp. Bath. u. Pharm., 1906, vol. 54. 

Delpeusch: These de Paris, 1880. 

Gathgens: Zbl. f. med. Wiss., 1875 and 1870. 

Gies: Arch. f. exp. Path. u. Pharm., 1877, vol. 8. 

Hausmann: Pfliigers Arch., 1906, vol. 113. 

Heffter: Arch, intern, de Pharmacodyn., 1905, vol. 15. 

Heffter : Arch. f. exp. Path. u. Pharm., 1901, vol. 40, p. 230. 

Heubner: Arch. f. exp. Path. u. Pharm., 1907, vol. 56, p. 370. 

Igersheimer u. Kothmann: Ztschr. f. Phys. Chemie, 1909, vol. 59, p. 256. 

lmjanitoff: Cited by Maly, 1901, p. 751. 

Konikofi': Cited by Maly, 1876. 

Kossel: Arch. f. exp. Path. u. Pharm., 187G, vol. 5. 

Luchsinger: Diss., 1875. 

Naunyn: Ziemssen's Handb., vol. 15, p. 350. 

Onaka: Ztschr. f. phys. Chem., 1911, vol. 70, p. 433. 

Pistorius: Arch. f. exp. Path. u. Pharm., 1883, vol. 16. 

Sehaier u. Bohm: Verh. d. Wiirzb. Ges., 1872, vol. 3. 

Stierlin: 1889. Cited by Stockman and Charteris. 

Stockman and Charteris, 1903. 

Weiske: Journ. f. Landwirtschaft, 1875. 

antimony and its compounds 
In many regions antimonial preparations are, like arsenic, em- 
ployed to improve the nutrition of cattle and to fatten them. As a 
matter of fact, the effects on the animal organism are qualitatively 
the same as those of arsenic, and differ from them only in degree 
and in the order in which the different effects occur. The same is 
true in regard to the effects on metabolism. In practice tartar emetic 
has been used in the same fashion as arsenic in the treatment of 



IRON AND MERCURY 415 

psoriasis, but at present it is used almost exclusively as an emetic. 
[Antimonial preparations were formerly much used, especially in the 
treatment of pneumonia, to slow the heart and lower the blood- 
pressure. These effects appear to be due to a direct depressing toxic 
action on the heart muscle and to an action on the blood-vessels 
similar to that of arsenic. At the present time no one would think 
of using these drugs for such purposes. — Tr.]. 

BIBLIOGRAPHY 
Giithgens: Zbl. f. d. med. Wiss., 1876. 

IRON 

Iron and its compounds may also be looked upon as exerting a 
direct specific action on the metabolism. This is evidenced by their 
well-established influence on the formation of the blood-cells (see p. 
440), as also by their "tonic action" in improving the general nutri- 
tion, which, although by no means definitely demonstrated, is generally 
accepted by clinicians. Moreover, its importance as an element essential 
to all plant life has been certainly established (Molisch), while Fromme 
has found that it favorably influences the growth of bacteria. Iron also 
appears to play a role in the activity of many enzymes (Sacharoff). 

The toxic actions of iron resemble those of arsenic and antimony 
[but, owing to its slow absorption, they never occur except under 
laboratory conditions. — Tr.]. 

BIBLIOGRAPHY 

Fromme: Diss., Marburg, 1891. 

Molisch: Sitz.-Ber. d. k. Akad. d. Wiss. zu Wien, 1894, vol. 103. 

Sacharoff: Jena, 1902. 

MERCURY 

It has long been known that patients undergoing a prolonged treat- 
ment with mercury often gain markedly in weight (Liegeois), and 
this has been confirmed by experiments on animals, in which, when 
very small doses of HgCL are taken for a long time, growth is 
stimulated and the body weight increased, while the red blood-cells 
increase in number (for lit. see Schlesinger) , even though in an ex- 
periment of but a few days' duration the metabolic balances may 
furnish no evidence of such effects. 

In chronic mercurial poisoning or mercurial cachexia, we see the 
results of directly contrary actions, — namely, acceleration of cell 
decay and inhibition of oxidation. The severe nephritis, which de- 
velops almost immediately in acute mercurial poisoning, makes it 
impossible to demonstrate these effects by determination of the nitro- 
gen balance as has been done for As.O.,. However, the disappearance 
of glycogen, the appearance of lactic acid, and the fatty infiltration 
of the various organs indicate that qualitatively the toxic action is 



416 PHARMACOLOGY OF THE METABOLISM 

essentially similar to that of arsenic. Mercurial poisoning, however, 
is differentiated from the latter by a more extensive destruction of 
the erythrocytes (Kaufmann) and by changes in the bones, which 
become poorer in lime salts and thinner and more brittle (Prevost, 
Heilborn). 

Presumably this power of causing tissue degeneration is of essen- 
tial importance in connection with the employment of mercury for 
the purpose of causing the rapid disappearance of syphilitic erup- 
tions and new growths, which even when untreated show but slight 
tendency to persistence. It has been shown by Justus that mercury 
reaches the capillaries and permeates the cells of these lesions. Still 
more important, however, just as is the case with arsenical compounds, 
is the etiotropic action on the Spirocha?ta pallida (see p. 540) . 

Chronic mercurial poisoning may develop and lead to most dis- 
astrous results in patients undergoing long-continued mercurial treat- 
ment or in individuals working in certain occupations in which they 
are exposed to the danger of continual absorption of mercury. 
Among such are workers in quicksilver mines, in mirror and ther- 
mometer factories, etc. 

As a rule, the first symptoms of chronic poisoning are similar 
to those of subacute poisoning, — salivation, stomatitis, and diarrhoea, 
to which are superadded very characteristic disturbances of the cen- 
tral nervous system. A condition of extreme psychic irritability, 
erethismus mercurialis, develops, and the patients become anxious and 
readily embarrassed or frightened, and not infrequently active mania 
may develop. A mercurial tremor of the muscles of the face and 
extremities develops, at first occurring only during voluntary move- 
ments but later occurring spontaneously and even during sleep. 
Finally, clonic convulsions may occur, which are occasionally ac- 
companied by epileptiform attacks and hallucinations of hypo- 
chondriasis or other psychic disturbances. At the same time the 
nutrition is rapidly impaired and pronounced cachexia develops, and 
the patient becomes anasmic and the skin and muscles flabby. Not 
infrequently the jaw-bones undergo necrosis similar to that occurring 
in phosphorus poisoning. 

Intercurrent diseases, most frequently phthisis, usually cause death 
when such conditions have developed. If, however, the patients are 
not too seriously poisoned and the absorption of the mercury is 
checked, by stopping its administration or by removing the patients 
from the mercurial environment, recovery may ensue after a time, 
but in some cases certain of the symptoms may persist indefinitely 
(Kussmaul) . 

BIBLIOGRAPHY 

Heilborn: Arch. f. exp. Path. u. Pharm., 1878, vol. 8. 

Justus: Arch. f. Derm. u. Syph., 1901, vol. 57. 

Kaufmann, C: Die sublimatintoxikation, 1888, here literature. 



CERTAIN PHASES OF METABOLISM 417 

Kussmaul: Untersueh. lib. d. konstitution. Mercurialismus, 1861. 

Liegeois: Gaz. des Hopitaux, 1869. 

Prevost: Rev. Med. de la Suisse rom.., 1S82. 

Schlesinger : Arch. f. exp. Path. u. Pharrn., 1881, vol. 13. 

LECITHIN 

In this connection it should be mentioned that, according to 
Danilewsky, frogs' eggs and larvae grow and develop more rapidly 
under the influence of lecithin than under normal conditions. Cron- 
heim and Mutter assert that the addition of lecithin to the diet of 
nurslings is followed by an increased assimilation of proteid (also 
Gilbert et Founder, Slowizoff). 

[Lest such statement should lead to an exaggerated idea of the 
value of the lecithin preparations, which are so widely exploited to 
the profession, the reader is reminded that lecithin is a constituent of 
many articles in our usual diet. The yolk of eggs, for example, con- 
tains it in large amounts. — Tr.]. 

Cronheim u. Miiller : Jahrb. f . Kinderheilk., 1900, vol. 2, Sept. 
Danilewsky: La Sem. Medicale, 1896, No. 2. 
Danilewsky: Fortschr. d. Med., 1896, No. 20. 
Gilbert et Fournier: Progr. medic, 1901, p. 129. 
Slowtzoff: Beitr. z. chem. Phys. u. Path., 1906, vol. 8, p. 370. 

DRUGS AFFECTING CERTAIN PHASES OF METABOLISM 
Thus far in this chapter the total metabolism has been discussed 
as if it were something without complexity, serving, as it were, as a 
general expression of the intensity of vital processes and growth 
of the cells of the body. Such a summary consideration is, however, 
no more and no less justifiable than is, for example, the general dis- 
cussion of the narcosis of living cells. The essentialities of such a 
phenomenon may be observed, it is true, on all cells, whether differ- 
entiated or not, and may be considered from a general standpoint, but 
there exist in individual instances the greatest quantitative differences 
in these effects, corresponding to the chemical and functional differen- 
tiation of the different cells. The same holds true for the actions of 
the "metabolic drugs" thus far discussed, and already we have 
noted certain striking differences in the degree and manner in which 
the metabolism of different cells may be affected by different drugs. 
Such, for example, are the. ('.specially predominant actions exerted on 
the bones by such drugs as phosphorus, antimony, and arsenic, or by 
such internal secretions as those of the thyroid, the hypophysis, and 
the sexual glands, while the marked influence exerted by iron on the 
haematopoietic organs is another instance of such specialized action. 
However, not only do the different types of cells exhibit such 
differences in their reactions to these various " metabolic drugs," 
but the different integral constituents of the cells also manifest 
similar differences in their reaction to them. It is, therefore, necessary 
27 



418 PHARMACOLOGY OF THE METABOLISM 

in this connection to consider more or less individually not only the 
cell as a whole, but also the organic energy-producing complex, as 
well as the catalyzers of the cells, their enzymes, their nuclear sub- 
stances, and their mineral constituents. 

However, right here we find our knowledge especially deficient, 
for, with the exception of a slight knowledge of the mineral metabo- 
lism of the cells, such, for example, as the action of Hg and of 
acidosis in removing Ca from the body and that of P and As in 
causing its assimilation (Falta), we know almost nothing about any 
regular orderly influencing of the special phases of metabolism by 
pharmacological agents. 

CARBOHYDRATE METABOLISM 

Diabetes Mellitus. — One of the most important of such dis- 
turbances of one phase of the metabolism is that which occasions a 
faulty utilization of the carbohydrates, whether this be due to the 
fact that the carbohydrates taken in the food or those formed from 
proteid are not stored up and retained in the form of glycogen and 
fat, or results from the inability of the actively functioning body cells 
to assimilate and utilize them as sources of energy. In either case the 
amount of the carbohydrates (usually glucose) present in the blood 
increases above the limit which can be kept back by the kidney, and 
consequently it is excreted in the urine without being utilized by the 
body. A discussion of the possible causes of these hyperglycaemic 
forms of diabetes is of no value for our present purposes, for it has 
not yet been possible to obtain any satisfactory and proven explana- 
tion of the manner in which these conditions may be influenced 
by drugs. Empirically it has been definitely established that the ad- 
ministration of certain drugs, alkalies, opium in large doses, jambul, 
and salicylic acid, lessens the excretion of sugar (Ka\ifmann) . 

According to J. Rudisch, the tolerance for carbohydrates is increased by 
atropine sulphate, as also by larger doses of the less poisonous atropine- 
methylium bromide (8 mg. t. i. d. ). Cavazzani and Soldaini conclude from their 
experiments that atropine paralyzes those nerves in the liver which excite the 
formation of glycogen. 

Toxic Glycosurias. — In poisoning due to many different agents, 
hyperglycemic glycosuria occurs as a temporary symptom. Among 
these are all poisonings causing asphyxia, whether due to depression 
of the respiratory centre, such as is caused by narcotics, or to paraly- 
sis of the respiratory muscles, such as may be caused by curare, or 
to interference with the function of the haemoglobin of supplying oxy- 
gen to the tissues, which may result from the actions of Wood 
poisons, particularly carbon monoxide. That the asphyxia is the 
cause of all these glycosurias is proven by the fact that in these 
intoxications the glycosuria may be prevented by the free admin- 
istration of oxygen wherever this may still be utilized, which evidently 



CARBOHYDRATE METABOLISM 419 

is not the case in poisoning due to the "blood poisons" (for lit. 
see Loewi). Apparently such asphyxial glycosurias are essentially 
caused by a stimulation (by the asphyxial blood) of the " piqure 
centre " in the medulla, for after section of the splanchnic nerves it 
does not occur. 

The glycosuria which may be caused by caffeine should be men- 
tioned in this place, for it, too, is prevented by section of the 
splanchnic nerves and is evidently due to direct stimulation of this 
' ' diabetes centre, ' ' which, like the other medullary- centres, is directly 
stimulated by caffeine. 

It would appear that glycosuria due to hyperglycemia may also 
result from the asphyxial stimulation of a peripheral " hypergly- 
cgemia-producing " mechanism, for in carbon monoxide poisoning 
glycosuria occurs even after section of the splanchnics. 

Suprarenal Glycosuria. — Recent investigations have furnished 
a satisfactory explanation of the manner in which the stimulation of 
the diabetes centre produces a glycosuria. The subcutaneous and, 
under some conditions, the intravenous injection of epinephrin, the 
active principle of the suprarenal gland, causes a glycosuria of con- 
siderable intensity. Waterman and Smith have shown that the 
epinephrin content of the blood is increased after the piqure glyco- 
suricque, while A. Meyer has demonstrated that after extirpation 
of the suprarenals the piqure does not cause glycosuria. It has also 
been shown that after extirpation of these glands or section of their 
nerves caffeine no longer causes an increase in the sugar content of 
the blood. It would therefore appear that, like the piqure, all toxic 
stimulations of the diabetes centre produce glycosuria in the last in- 
stance by an action on the adrenals. 

Phloridzin Glycosuria. — A glycosuria of entirely different type 
is caused by the internal, subcutaneous, or intravenous administration 
of phloridzin .* Its effect may be briefly stated to be the lowering 
of the renal threshold value for the excretion of sugar from the 
blood, — i.e., its power of so altering conditions in the blood or the 
kidney that the kidney excretes sugar when the blood contains less 
than normal amounts. The nature of this change is not at all clear, 
but it is at least certain that it is a local change taking place in the 
kidney. Possibly it consists in an exaggeration of a normally prac- 
tically imperceptible power of Hie renal parenchyma to Form or split 
off sugar from some other substances or some sugar-containing com- 
pound normally present in the blood. 

Other Types of Renal Glycosurias. — Glycosuria may also result 
from the administration of many poisons which, like uranium, the 
chromates, corrosive sublimate, and cantharidin, produce visible 
changes in the renal parenchyma. As in these glycosurias it has 
been shown that hyperglycsemia occurs only to a. very sligh t degree 

* A glucoside present in the bark of the roots of apple and cherry trees. 



420 PHARMACOLOGY OF THE METABOLISM 

and by no means regularly,* it may be concluded that they are due 
to a diminished power of the kidney to prevent the passage of sugar 
from the blood into the urine. 

Formation of Glucuronic Acid. — A quantitative alteration of the 
carbohydrate metabolism — namely, the increased excretion of the 
esters of glycuronic acid — results from the administration of a large 
number of different organic substances, among which are certain 
much-used drugs, such as chloral hydrate, phenol, camphor, many 
antipyretics, morphine, and others too numerous to mention. 

Glucuronic acid is chemically very closely related to glucose, its 
relation being that of an acid to its corresponding alcohol, as shown 
by the accompanying formulas: 

COH(CHOH) 4 COOH, glycuronic acid, 
COH(CHOH) 4 CH,OH, glucose. 

In the body it occurs only in organic combination, chiefly with 
some alcohol or with phenol. L T nder normal conditions very small 
quantities of it are formed, and are combined with such products 
of intestinal putrefaction as indol, phenol, etc., and are execreted in. 
such combinations by the kidney. After administration of the above- 
mentioned substances, which in the body are reduced or oxidized to 
phenols or alcohols, the glycuronic acid is formed in increased 
amounts, or is not further combusted, as is perhaps normally the- case, 
and consequently larger amounts are excreted in the urine organically 
combined with these substances. Glycuronic acid is probably not 
derived from carbohydrates already formed and present as such in 
the body, but, like glucose, is probably formed from certain mother 
substances contained in the proteid molecule, some of which are 
changed into glucose and others into glycuronic acid. The former is 
transformed into and stored up as glycogen, while the latter is 
instantaneously combusted unless it is protected therefrom by ester- 
fication (Fenyvessy). 

These combined glycuronic acids reduce alkaline copper solutions (as a 
rule, only if previously decomposed by boiling with acids) and are lffivorotatory, 
although free glycuronic acid is dextrorotatory. 

BIBLIOGRAPHY 

Cavazzani e Soldaini: Arch. Ital. de Biol., 1896, vol. 25, p. 465. 

Falta: Volkmann's Vortriige, 1905, No. 405. 

Fenyvessy: Arch, intern, de Pharmacodyn., 1903, vol. 12, p. 407. 

Kaufmann: Ztschr. f. klin. Med., 1903, vol. 48. 

Loewi: v. Noorden's Handb. d. Path. d. Stoffw., 1907, vol. 2, p. 711. 

Meyer, A.: Compt. rend. Soc. Biol., 1906, p. 1123. 

Rudisch, J.: Arch. f. Verdauungskrankh., vol. 15, p. 479. 

Waterman and Smith: Pfliiger's Arch., 1908, vol. 124. 

*HgCL: Graf, Diss. Wiirzburg, 1895; Richter, Ztschr. f. klin. Med., 1900. 
Bd. 41. Chromates: Kossa, Pniiger's Arch., 1902, Bd. 8S; Blanck, Med. klin., 
1905. Uranium: Blanck, loc. cit. ; Fleckseder, Arch. f. exp. Path, und Pharm., 
J 906, Bd. 56. Cantharidin: Richter, Deut. med. Woch., 1899, No. 51; Pollak, 
Arch. f. exp. Path, und Pharm., 1909, Bd. 61, and 1911, Bd. 64. 



PURINE METABOLISM 421 

Acidosis. — Many variations and disturbances may occur in the 
chemical decomposition of the tissues and food-stuffs, by which ordi- 
narily the end products of metabolism are formed. While these 
variations from the normal at times produce hardly appreciable effects 
in the total energy balance, they may have results which are of great 
importance for the welfare of the organism. Thus, the formation and 
excretion of abnormal amounts of acids, which occur in poisoning by 
various agents, result only in a slight loss of energy, but, under some 
conditions, may so alter the chemical conditions throughout the whole 
body as to produce most serious results. 

PURINE METABOLISM 

The metabolism of the purines, pathological disturbances of which 
express themselves as gout, is of especial practical importance. Little 
is known of their causation, and consequently any successful treat- 
ment of these causes, in so far as this is actually possible, rests on no 
rational foundation. The first assumption naturally made, that the 
excretion of the uric acid retained in the tissues and in the blood 
could be hastened and increased by the administration of alkalies 
and other uric-acid solvents (piperazine, lysidine, etc.), has been found 
to be erroneous. While the salicylates increase the excretion of uric 
acid, they do not exert any material influence on the course of the 
disease (for lit. see TJlrici and v. Noorden). 

Atophan. — The investigations of Nicolaier and Dohrn have shown 
that the excretion of uric acid is markedly increased by the admin- 
istration of the different quinoline-carbonic acids and their derivatives. 
2-Phenylquinoline-4 carbonic acid, to which the trade name of 
atophan has been given, possesses this power to an especially high 
degree. According to Weintraud and other clinical observers, very 
favorable results may be obtained in cases of gout by the admin- 
istration for long periods of 0.5-1.0 gm. of this drug three or 
four times daily. Large quantities of alkaline waters should be 
drunk during this treatment, in order to prevent the deposition of 
uratic concretions in the kidney or bladder. 

Xo drugs are known which have any power of influencing those 
anomalies of metabolism known as oxaluria and phosphaturia. 

BIBLIOGRAPHY 
Nicolaior u. Dolirn: Dout. Arch. f. klin. Med., 1908, vol. 93, p. 331. 
v. Noorden: Eandb. d. Path. d. Stoffw., L906, p. 131. 
Ulrici: Arch. I exp. Path. u. Pharm., 1901, vol. 40, p. 321. 
Weintraud: Ther. d. Gegenw., 1911, p. 97. 



CHAPTER XIII 

PHARMACOLOGY OF THE MUSCLES 

PHYSIOLOGY AND ANATOMY 

There are three types of muscle-cells present in the body, — the 
9triated or voluntary, the smooth or involuntary muscles, and the 
cardiac muscles, all differing from one another in their chemical 
composition, their histological structure, and their physiological 
functions. 

The effects of pharmacological agents on the smooth and the 
cardiac muscles, the vegetative muscle, has been discussed in the 
chapters dealing with the pharmacology of the circulation and of the 
vegetative nervous system. Here a direct action on the muscles them- 
selves could only very seldom be assumed with certainty, for, as a rule, 
the actions discussed affected the terminal nervous organs (nerve- 
endings) or the myoneural intermediary substance which does not 
actually belong to the integral substance of the muscle-cells, even 
though it does not degenerate after section of the nerves. In the 
case of certain pharmacological actions this was apparent from the 
peculiar effects of the drugs, which were explained by the character 
of the innervation, so that they expressed themselves, as in the case 
of epinephrin, sometimes as stimulation and sometimes as inhibition, 
while similar phenomena were also observed in connection with the 
actions of the group of " autonomic poisons." The only pharma- 
cological substances which probably stimulate all the smooth muscle 
cells in the body are the substances of the digitalis group and the 
salts of barium. 

The functional capacity of the striated muscles is, like that of the 
smooth muscles, dependent in general not only on the structure and 
chemical composition of their organic constituents, — proteids, lipoids, 
and carbohydrates, — but also, on their inorganic constituents, 
especially the cations (Hober). Thus, Overton has shown that the 
excitability of muscles is entirely abolished when Na ions are with- 
drawn from them or from the fluid between their cells by a?qui- 
molecular sodium-free solutions, such as cane-sugar solutions, while 
Loeb has shown that it is tremendously increased by removal of the 
calcium ions. This latter is of toxicological interest in so far as the 
fibrillary muscle twitchings in poisoning by agents which precipitate 
calcium (oxalic and citric acids) may be attributed to the removal 
of calcium. 

It is also certain that the water content of muscles distinctly in- 
fluences their functional capacity (Demoor et Philippson), extreme 
dehydration having a marked effect, as will be shown. Probably 
422 



PHYSIOLOGY AND ANATOMY 423 

an abnormally large water content will also have a harmful effect. 
One of the ways in which this may be induced is by appropriate feed- 
ing, Tsuboi having found in rabbits, fed chiefly on potatoes, the water 
content of the muscles 2-7 per cent, higher and their haemoglobin con- 
tent 2-4 per cent, lower than that of normal controls. 

The water content of muscle is diminished by work, the relative 
increase of the dry material being the most important factor in the 
hypertrophy resulting from work, except in the case of the cardiac 
muscles, which alone when hypertrophied show only a general in- 
crease in weight without any alteration in the proportion of their 
constituents ( Gerk artz). 

The voluntary muscles are the organs for motion and for produc- 
tion of heat. Their fibres are composed of the apparently homo- 
geneous sarcoplasma and, imbedded therein, the anisotropic trans- 
versely striated fibrils. According to the relative amounts of these 
two elements (Griltzner) or their reciprocal arrangement (Paukul), 
two types of muscle-fibres may be differentiated, — those richer in 
plasma, the so-called red muscles, which can remain contracted for 
long periods, and those containing less plasma, the so-called white 
muscles, which contract and relax quickly (Ranvier, Erb). The 
quickly acting elements are the anisotropic fibrils and the slowly 
acting the sarcoplasma (Botazzi, Joteyko). 

These two elements appear to have entirely different chemico- 
physical properties and equally different physiological and pharma- 
cological reactions. While the rapid twitchings of the fibrils are ac- 
companied by an active production of heat and marked chemical 
changes, and accordingly relatively soon result in exhaustion, — that 
is, in the consumption of the readily available substances and the pro- 
duction of "fatigue substances," — the slowly starting and persis- 
tent shortening of the sarcoplasma, which at times may last for hours 
or even weeks (as in contractures), appears to cause no measurable 
production of heat (Brissaud) . It would appear, therefore, that this 
latter type of contraction represents only another physical state and 
normally exhibits none of the ordinary phenomena of fatigue. This 
is especially remarkable in persistent hysterical contractures. 

Both these types of muscular contractions are under the control 
of the nervous system, and are without doubt governed by separate 
and distinct mechanisms, or at least by different stimuli, which in 
the case of voluntary movements are excited in the central nervous 
system and which may cause either short contractions or a more or 
less persistent contraction, depending on the character of the stimulus. 
The effective artificial stimuli are also different, the quick shocks of 
Hit- induced current exciting the anisotropic fibrils, and the constant 
current, the sarcoplasma. 

Chemical si i initial ion of a nerve 1 — as, for example, by concentrated 
salt, solution applied to the nerve of a frog's musclc-nervc prepara- 




424 PHARMACOLOGY OF THE MUSCLES 

tions — excites chiefly the persistent contraction of the sarcoplasma, to 

which may be superadded twitchings of the fibrillary substance, these 

being especially well developed if such twitchings are periodically 

induced by the induced current (Fig. 47) 

(Limbourg). 

Direct and Indirect Pharmacological 
Actions. — From the above, it is clear that 
the functional activity of the muscles may 
be influenced by pharmacological agents 
acting either directly on the muscles or 
by Kci. ^fZ^n^Z through the nervous system. As is well 
electric stimulation every io sec- known, the ability of a muscle to contract 

onds. ' ^ . 

depends almost entirely on the nervous im- 
pulses which are constantly reaching it, even when they cause no per- 
ceptible contractions. This is most strikingly shown by the much 
more rapid occurrence of rigor (either rigor mortis or that of toxic 
origin) in muscles with intact nerves than in those deprived of their 
nerves, or, what is essentially the same thing, in curarized muscles 
(Kerry). 

It is, therefore, conceivable that, in conditions of purely muscular 
weakness or lessened functional power of the muscles, the strengthen- 
ing of the reflex motor influences, or their facilitation by such drugs 
as strychnine or by electric stimulation of the motor nerves, may 
not only subjectively facilitate muscular action, but, by continuously 
keeping the nerve paths open (Bahnung), may also maintain and 
stimulate the chemical processes on which muscular contraction and 
activity depend (Robertson) . 

Contracture. — If a muscle becomes fatigued by continuous exer- 
tion or by maximal tetanic contraction, the excitability of the sarco- 
plasma — or, more correctly expressed, its tendency to shorten — is in- 
creased, the muscle passing into the well-known permanent shortening, 
Tiegel's contracture. In frogs, which at the end of the winter are in a 
state of malnutrition, this condition develops very readily, so that their 
muscles often, after a single powerful stimulation, contract and re- 
main contracted for a considerable period. In myotonia congenita, 
or Thompson's disease, the muscles behave similarly, the muscle tone 
being absent during persistence of these contractures, as is also the 
case with hysterical contractures (Herz). In this condition also 
the sarcoplasma is not normal, exhibiting under the miscroscope an 
abnormal structure (S chief 'er -decker) . An analogous disturbance is 
found in many other diseases of the muscles — e.g., in pseudohyper- 
trophic muscular paralysis (Mendelsohn) and in athetosis (Kaiser). 
This pathological condition may be induced by dehydration — by con- 
centrated salt solutions or glycerin (Santesson, Gregor), as also 
by numerous poisons, but in an especially striking way by veratrine. 



VERATRINE 425 

BIBLIOGRAPHY 

Bottazzi: Dubois' Arch., 1901, p. 377. 

Brissaud et Regnard: Bull. Soc. Biol., 1881, vols. 13-14, p. 348. 

Demoor et Philippson: Bull, de l'Acad. d. Med. de Belg., 1908-09, p. 655. 

Erb: Die Thomsensehe Krankkeit. Leipzig, 1SS6. 

Gerkartz: Pfliiger's Arck., 1910, vol. 133, p. 397. 

Gregor: Pfliiger's Arck., 1904, vol. 101. 

Griitzner: Bresl. arztl. Zeit., 1883-1886. 

Herz: Wien. klin. Wock., 1900, p. 1178. 

Hober: Pfliiger's Arck., 1904, vols. 101-102. 

Hober: Pfliiger's Arck., 1905, vol. 106. 

Jotevko: Etude sur la contrac. tonique, etc., Inst. Solvay Trav., 1902, vol. 5, 

p. 229. 
Kaiser: Neur. Zbl., 1S97, Xo. 15, vol. 16, p. 674. 
Kerry u. Rost: Arck. f. exp. Path. u. Pharm., 1897, vol. 39. 
Limbourg: Pfliiger's Arch., 1S87, vol. 41. 
Loeb: Ffek's Festschrift, 1889. 

Mendelsokn : Compt. rend. Acad, des sciences, 1S83. 
Overton: Pfliiger's Arck., 1902, vol. 92. 
Paukul: Dubois' Arck., 1904, p. 100. 
Ranvier: Compt. rend., 1S73, vol. 77, p. 1030. 
Robertson: Biockem. Ztschr., 1908, p. 287. 
Santesson: Skand. Arck. pkys., 1903, vol. 14, p. 1. 

Schieferdecker u. Schultze: Deut. Ztsckr. f. Nervenkeilk., 1903, vol. 25. 
Tsuboi: Ztschr. f. Biol., 1903, vol. 44. 

VERATRINE 

Veratrine (Bolim), obtained from the seeds of Veratrum sabadilla 
and V. viride, is a mixture of alkaloids of which cevadine (Freund) 
is the most important. 

Locally it is very irritant to the sensory nerves, very small amounts being 
sufficient to cause sneezing, burning of the eyes, etc. Wlien rubbed into tbe 
Bkin, it first causes a painful pricking and burning sensation and later 
anaesthesia. Veratrine ointment has, therefore, been successfully employed in 
trigeminal neuralgia and sciatica. 

In connection with this action on the sensory nerve-endings it may be that 
this drug's action is not limited to these structures alone, for it must be 
admitted that it may possibly pass into and along the nerves and reach central 
portions of them, for Joteyko has made the remarkable observation that 
veratrine in the frog, unlike almost all other substances, can spread along 
in the nerves and relatively quickly transverse long stretches, even after 
complete stoppage of the circulation. This would explain the fact that, even 
after local application of this drug, paresthesias occur at remote points 
[Kunkel), as well as the fact that, in animals poisoned by its subcutaneous 
administration, the characteristic alteration of the phenomena accompanying 
stimulation, which may be observed in the muscle after veratrine, may be also 
demonstrated in the electromotor phenomena occurring in the nerves (Garten). 

Veratrine acts energetically on the central nervous system, causing vomit- 
ing, dyspnrea, and convulsions, and finally paralysis of the medullary centres. 

Action on Voluntary Muscles. — The most thoroughly investi- 
gated action of veratrine is that on striated muscle, which in warm- 
blooded animals manifests itself by peculiar spastic and difficult move- 
ments, while iii the frog this action is even more clearly developed. 

It' ;i frog he poisoned with ;i small amount (1/20 mg.) of veratrine, 
after a short time a characteristic alteration of its movements is noted, 
tbe Erog springing quite normally, but then lying for a time stretched 



426 PHARMACOLOGY OF THE MUSCLES 

out and only gradually becoming able to bend bis legs again and to 
pull them up. Tbe same muscular phenomena may be observed in 
nerve-muscle preparations, even after curarization ; contractions in ; 
duced by the induced current occur immediately, but either the 
muscle remains contracted or the contracted muscle after starting 
to relax promptly contracts again before it has completely relaxed 
and this time remains contracted for a considerable period 
(Mostinzki). If the stimuli follow each other rapidly, the contracture 
disappears, for the overexcitable sarcoplasma exhausts itself and 
breaks down, becoming under these conditions fatigued more quickly 
than the fibrillar substance, which ordinarily tires more readily (see 
Fig. 48). 

The increased extent of the contractions and the augmented pro- 
duction of heat indicate that not only the sarcoplasma but also the 




Fig. 48. — a, normal muscular contraction; 6, c, veratrine contractions; d, influence of 
fatigue on veratrinized muscle. 

fibrillar substance is rendered more excitable by veratrine, the total 
functional capacity of the muscle being increased, as was demon- 
strated by Dreser, using the frog's gastrocnemius. 

Other Actions of Veratrine. — Veratrine exerts a similar action on the cardiac 
muscle, the contraction being prolonged, or, better expressed, passing off more 
slowly. By this action on the cardiac muscle the pulse may be markedly 
slowed, and, as a result of a depression of the centres for the regulation of the 
temperature, the temperature may fall after the administration of this drug, 
which formerly was extensively employed as an antipyretic. The action on 
the heart and the muscles might well be therapeutically useful were it not for 
the fact that these eifects may usually be secured only by doses which produce 
a profound poisoning of the central' nervous system and cause violent and 
dangerous disturbances of the circulation and respiration. It was formerly 
used in the dangerously large amounts of 0.05 gm. for single doses and 0.2 gm. 
per diem. 

Veratrum viride and V. album contain protoveratrine, an alkaloid 
related to veratrine but much more dangerous (Eden, Salzberger). 



STRYCHNINE 427 

Its actions differ considerably from those of veratrine, but no benefit 
is to be expected from its therapeutic employment. 

[There is good ground for believing that veratrine slows the 
pulse in man as a result of central vagus stimulation rather than as 
a result of its typical action on the cardiac muscle. This drug is 
also used by competent authorities in the treatment of uraemia and 
of eclampsia, particularly -when the blood-pressure is high. Under 
these conditions it often markedly lowers the blood-pressure. How- 
ever, the weight of opinion appears to be against its employment for 
these indications. — Tr.] 

BIBLIOGRAPHY 

Bohm: Arch. f. exp. Path. u. Pharm., 1908, vol. 58. 

Dreser: Arch. f. exp. Path. u. Pharm., 1890, vol. 27. 

Eden: Arch. f. exp. Path. u. Pharm., 1892, vol. 29. 

Fick u. Bohm.: Wiirzb. Arb., 1872. 

Freund u. Schwarz: Ber. der Deut. Chem. Ges., 1S99, vol. 32, p. 800. 

Garten: Pfluger's Arch., 1899, vol. 77. 

Jotekvo: Inst. Sol. Trav., etc., 1902, vol. 5, p. 271. 

Kunkel'a Handbuch, 1901, p. 765. 

Mostinski: Arch. f. exp. Path. u. Pharm., 1904, vol. 51. 

Salzberger: Arch. d. Ph., 1890. 

Strychnine. — Paderi states that the tone of a frog's gastroc- 
nemius, isolated from the central nervous system, is augmented by 
very small doses of strychnine, the extent and duration of its con- 
tractions being increased, and that the same is true for the muscles 
of the frog's stomach. These observations appear to him to support 
the clinical employment of very small doses of this drug as a so- 
called " tonic." 

BIBLIOGRAPHY 

Paderi: Arch. Ital. Biol., 1893, vol. 19, and La Terap. Med., 1892. 

Of much greater practical importance than the above-described 
qualitative alteration of muscular action, produced by veratrine, is 
the causation by drugs of a quantitative alteration of the functional 
capacity of the muscles, as measured by the extent to which they can 
contract and by their absolute power, — i.e., the largest weight they 
can lift. 

MUSCULAR DEPRESSANTS 

A diminution of their functional capacity, even to complete paral- 
ysis, is, as is well known, a symptom of many neuromuscular patho- 
logical conditions, and is usually associated with atrophy or degenera- 
tion of the muscles. Experimentally, also, such paralysis of the 
muscle-fibres may be produced, particularly in cold-blooded animals, 
by the administration of apomorphine or salts of Cu, Pb, or As 
(Harnack). 

In chronic lead poisoning in man. a paralysis often occurs, especially in 
the extensors of the arm. Whether this he due primarily 1<> changes in the 
muscle-cells or in their nerves or to defeneration in the cord is still uncertain. 



428 PHARMACOLOGY OF THE MUSCLES 

The predisposition of the extensors of the arm to this affection is probably 
due to the greater use of these muscles, for in small children and in animals 
the paralysis caused by lead is atypical in its distribution, the lower ex- 
tremities being affected as frequently as are the upper {Stieglitz, Neumann, 
Edinger, Teleky). 

BIBLIOGRAPHY 

Edinger: Deutsche med. Woch., 1904, No. 45, p. 1633; 1904, No. 49, p. 1800; 

1904, No. 52, p. 1921. 
Harnack: Arch. f. exp. Path. u. Pharm., 1874, vol. 3, and 1878, vol. 9. 
Neumann, W. : Diss., Bern, 1883. 
Stieclitz: Arch. f. Psychiatrie, 1892, vol. 24, p. 50. 
Teleky, E.: Zur Kasuistik d. Bleiliihmung, D. Z. f. Nervenheilk., 1909, vol. 37, 

p. 234. 

MUSCULAR STIMULANTS 
Caffeine and theobromine and, although in a different manner, 
alcohol may increase the working power of muscle. 

CAFFEINE 

In frogs — especially readily in E. temporaria (Schmiedeberg) — 
large doses of caffeine cause a maximal shortening and rigor of the 
muscles, which may be observed equally well in the muscles of the 
intact frog or under the microscope in teased muscle preparations 
at the moment of contact with a solution of caffeine. Rigor may also 
be induced in warm-blooded animals by injecting caffeine into an 
artery (Lakur). 

With less pronounced caffeine action there is an increase in the 
muscle's irritability and ability to contract when stimulated, so that 
it not only responds to a slighter stimulus (Paschkis), but exhibits a 
greater capacity for work and an increase in absolute power (Dreser). 
Xanthine and creatin produce similar effects. In man also this drug 
increases the capacity for muscular work, as has been shown chiefly 
by exact ergographic investigations. 

Muscular Fatigue. — Various parts of the neuromuscular appara- 
tus are involved in the phenomena of fatigue, the intramuscular 
nerve-endings and the muscle-cells being primarily affected, and 
secondarily the psychomotor functions of the central nervous system 
(Joteyko). Both psychophysical investigations (Krdpelin) and the 
mathematical analysis of ergographic fatigue curves (Henri) indicate 
that the height of the lift is chiefly dependent on the condition of the 
peripheral neuromuscular organ, while the number of contractions 
which take place before complete exhaustion occurs depends on the 
condition of the motor centres. That is to say, in myogenic fatigue 
the height of the lift immediately or very quickly diminishes some- 
what and then falls very gradually, while in central fatigue the 
height of the lift is at first normal but very rapidly falls to zero, 
so that the number of liftings accomplished is much less than is nor- 
mally the case (Fig. 49). 



CAFFEINE AND ALCOHOL 



429 



Effect of Caffeine in Fatigue. — In fatigue, when the capacity for 
muscular work is already diminished, caffeine increases the total per- 
formance of muscular work. This is due chiefly to a direct beneficial 
action on the muscle-cells (Mosso), and to some extent to its favorable 
action on the central motor functions (KrapeUn, Koch). 




Fig. 49. — Ergographic curves. 

These observations furnish a confirmatiou of the experience of 
mountain-climbers and soldiers, who long ago discovered the power 
of coffee, tea, etc., to overcome fatigue during exhausting exertion 
or marches. Creatin, which is a constituent of meat broths, influences 
the muscle function similarly to, though less powerfully than, caffeine. 



BIBLIOGRAPHY 
Dreser: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 50. 
Henri u. Joteyko: Compt. rend. Acad, des sciences, Paris, 1903. 
Joteyko: Art. "Fatigue," in Richet, Diet. d. phys., here compl. lit. 
Koch: Ergographische Studien, Diss., Marbourg, 1S94. 
Kr&pelin u. Hoch: Psycholog. Arbeiten, 1895. 
Lakur: Virchow's Arch., 1895, vol. 141, p. 479. 
Mosso, U.: Arch. ital. biol., 1893, vol. 19. 
Paschki8 u. Pal: Wien. med. Jahrb., 1880, p. 611. 
SehmieJeberg: Arch. f. exp. Path. u. Pharm., 1873, vol. 2. 



ALCOHOL 

The action op alcohol on muscle function is much more com- 
plicated. That in man small amounts of alcohol (0.3-0.5 gm. per 
kilo, body weight) may under some conditions facilitate intense 
muscular activity and increase the power of performance is well 
known, but it is equally well known that they may produce a directly 
opposite effect. These effects result from the action of alcohol on the 
central nervous system and on the muscles and the nerve-endings. 

Action through the Central Nervous System. — Tn a previous sec- 
tion (Pharmacology of the Central Nervous System) it has been shown 
that one of the early actions of alcohol is, on the one hand, to facilitate 



430 PHARMACOLOGY OF THE MUSCLES 

the excitation of motor impulses and, on the other, to blunt the percep- 
tion of sensory stimuli. Muscular activity may be favorably in- 
fluenced both by the facilitation of the central psychomotor processes 
and by the more or less complete suppression of the fatigue reflexes 
resulting from muscular exertion {Frey). 

Direct Action on Muscle. — Alcohol exerts two actions on the 
muscle itself which are antagonistic to each other. The capacity 
of the muscles for work and perhaps also their readiness to contract 
are, in warm-blooded animals, somewhat unfavorably influenced 
from the start, as shown by W. Lombard and by Frey for the flexors 
of the forearm in man. 

Schcffer found that at first alcohol caused an increase of the excitability 
of the frog's nerve-muscle preparation, which did not occur with curarized 
preparations. Vereas, using somewhat longer dosage, obtained the same in- 
crease of excitability, even after curare, and an augmentation of functional 
power. These effects were produced both by methyl alcohol ( 1/80 of the body 
weight) and by ethyl alcohol (1/500-1/200 body weight). Larger doses had a 
harmful effect, which was less marked with methyl than with ethyl alcohol. 




Normal curve. Alcohol curve. 

Fig. 50. — Interval four seconds. 

In spite of this, however, alcohol may increase the total perform- 
ance of a muscle not by increasing the power or extent of the in- 
dividual contractions, but by increasing the endurance of the muscle, — 
i.e., increasing its ability to recuperate after each contraction. As a 
result of this action, exhaustion from continuous and therefore rapidly 
exhausting work is distinctly postponed. Joteyko's ergographic curves 
(Fig. 50) illustrate this well. In isometric tasks also the total per- 
formance is increased (Hellstcn). 

The increased recuperative capacity of muscles treated with alco- 
hol is hardly susceptible of explanation except on the premise that 
alcohol furnishes food and energy to the muscles. This has been 
assumed by Frey, Schnydcr, and Joteyko, and is confirmed by the 
mathematical analysis of Durig's experiments, in which he determined 
the effects of alcohol on the respiratory coefficient and the production 
of energy. If alcohol, which is readily oxidized to C0 2 and H.O, is 
oxidized in place of other constituents of muscle, it is clear that there 
will be found smaller amounts of those decomposition products of the 
cellular material whose accumulation plays an important role in the 
causation of fatigue. The analysis of Joteyko's alcohol muscle curves 
speaks strongly for this view. 



ALCOHOL AS FOOD 431 

Joteyko sets up the following equation, n = H -\- bt 2 — at 3 — ct, as one con- 
stantly true for ergographic curves, in which n = the ordinate, the height of the 
lift; £:=the abscissa, the interval of time; H = the height of the lift at the 
start, and a, b, and c are variables, a representing the formation of " fatigue 
substances," 6 the central motor facilitation, and c the consumption of the 
muscle's store of carbohydrates and reserve materials. With the use of this 
formula it may be shown that in the curves obtained under the influence of 
alcohol the value of a (i.e., the formation of fatigue substances) is smaller than 
in normal curves. 

A. Fick opposes the assumption that alcohol is combusted and supplies 
muscular energy, by objections based on mathematical calculations which 
indicate that in fatigue, as it occurs in ergographic experiments, no marked 
lessening of the supply of carbohydrate fuel can occur, and, therefore, there 
is no ground for concluding that muscular recuperation under the influences of 
alcohol is due to supplying the lacking fuel. The correctness of this criticism 
cannot be experimentally tested, for we do not know whether all the energy- 
supplying material in the muscles (carbohydrates) is equally readily available. 
Probably this is not the case, for it is possible to cause a complete disappearance 
of muscle glycogen only by extreme forced muscular contractions. This as- 
sumption is also rendered improbable by the marked diminution of the sugar 
in the blood which occurs during moderate muscular exertion at a time when 
the muscle certainly contains considerable glycogen (Wetland) . Fick's critique 
could be equally well used to disprove the recuperative effects of small amounts 
of sugar (30 gm. ) in extreme exhaustion. This latter has been certainly 
proved (Schumberg, Joteyko), and can hardly be explained otherwise than as 
the result of supplying energy. 

Alcohol a Food in Case op Need. — From the above discussion it 
is justifiable to conclude that alcohol will cause no objective increase 
of the working power of strong and unexhausted muscle although 
bringing about a subjective facilitation, while in conditions of exhaus- 
tion it will positively increase the failing muscular power. It may, 
therefore, be useful as a promptly though temporarily acting means 
of recuperation and strengthening in case of marked exhaustion from 
work which must not be interrupted. Under such conditions it is 
for the time being more effective than sugar or other food, for, on 
account of its solubility in lipoids, it is very rapidly absorbed and 
taken up by all the cells. 

Not a Complete Food. — Alcohol is, however, not a complete or 

even an approximately satisfactory substitute for food for muscle, 

for with larger doses, such as are necessary for the accomplishment 

of any considerable amount of work, its toxic action on the central 

nervous system becomes manifest and interferes with the power to 

work. Moreover, even with moderate not markedly toxic doses both 

Chauvcau and Durig have shown that the utilization of the energy 

, . energy produced 

produced is not good: ^ — — being much less than when 

energy utilized 

food containing no alcohol is taken. "With this fuel (alcohol) not 
only does the machine work more slowly than when the usual fuel 
ordinary food) is used, but, when the attempt is made to use alcohol 
as fuel, the machine itself is for the time being damaged and, utiliz- 
ing the available fuel uneconomically, performs less work than it 
should." It is not necessary to stale that under certain conditions 



432 PHARMACOLOGY OF THE MUSCLES 

the heat resulting from the combustion of alcohol may be of ad- 
vantage to the body by sparing other fuel material. 

The Bole of Alcohol as a Food. — Not only does the oxidation 
of alcohol supply heat to the body, but it also supplies energy which 
may be directly utilized by various organs in the performance of 
their functions. The effects of alcohol on the isolated heart (p. 259) 
have indicated this with a high degree of probability. For the whole 
body this fundamentally important question has repeatedly been 
the subject of investigations,* in which the tissue and energy changes 
in man and beast at work and at rest have been observed. In these 
experiments the attempt has been made to determine whether the 
administration of alcohol results in a sparing of other constituents 
of the body, especially of the carbohydrates and fats and indirectly 
of the proteids. 

Nearly all the authors who have occupied themselves with this question 
have concluded that alcohol, which is almost completely combusted in the 
body, may replace equivalent amounts of carbohydrates, fats, and proteids as a 
source of energy. 

Kassowitz, in a careful critique of these articles, has shown that there 
is still reason to doubt the significance and interpretation of many of the 
results of such investigations, such as the calculations of the amount of CO., 
produced, of 2 consumed, and of N excreted, as also of the directly determined 
caloric balances; but his critique based on such calculations can hardly be 
maintained to be satisfactory, in the face of Durig's experiments. Furthermore 
Kassowitz bases his denial of any nutritive properties of alcohol largely on 
theoretical hypothesis, as follows. He claims that the muscle-cell is not to 
be compared with a power machine run by heat resulting from the combustion 
of foodstuffs, but that, on the contrary, like all living cells, the muscle-cell is 
a labile complex, which is constantly being built up and broken down, 
assimilating the nutritive material brought to it and utilizing it to replace and 
build up anew its own protoplasm, producing heat and performing work by 
catabolism of its protoplasm and not by direct combustion of any sort of 
fuel which may be brought to it. As alcohol is not suitable material for 
these assimilative anabolic processes, it is useless, and is combusted in a sense 
outside of the protoplasm without utilization of the energy produced for the 
performance of work. It, therefore, cannot serve the cell as a source of energy 
as do the true foods, proteids, fats, and carbohydrates. 

This argument against the biological utilization of alcohol can no longer 
be considered as pertinent, since it has been established that alcohol is formed 
in normal metabolism as a result of the anabolism of the protoplasm. 
fttol-lasa's discovery, that animal and vegetable cells contained an enzyme 
which fermented carbohydrates with formation of C0 2 and alcohol, indicated 
with great probability that this was the case, although A. Harden and Maclean 
have since then raised a doubt as to the presence of such enzymes in animal 
tissues. Landsbcrg and Reach, however, have brought a direct proof of the 
presence of alcohol in normal tissues. The latter author found 0.0017 per cent, 
of free alcohol and small quantities of ethyl esters in rabbits' muscles, liver, 
and brain. As alcohol, therefore, is formed in the normal mechanism — i.e., 
according to Kassowitz, "biologically" — it is no longer to be doubted that its 
combustion may be of value to the cell. Whether the alcohol reaches the cell 
from the outside or is formed in it can make no fundamental difference. 

Alcohol, a Utilizable Food, with Limitations. — In general it may 
be said that alcohol is a food which is utilized rapidly, but that it 

* For the very voluminous literature bearing on this subject, see M. 
Kochmann u. W. Hall, Pfliiger's Archiv., vol. 127, p. 280. 



ALCOHOL AS FOOD 433 

is a poor food, to be used only in case of need, for the following 
reasons. Its potential energy is less economically utilized in the 
performance of work than is that of other food-stuffs, it cannot be 
stored up as a reserve to be used as need arises, but, under all cir- 
cumstances, must be combusted at once, and, above all, it is poisonous. 
A slight degree, although not always a harmful one, of toxic action 
is produced whenever alcoholic beverages are used as stimulants or 
as food. In spite of this, it may often happen that, when other foods 
may not be administered, — as, for example, in septic febrile cases 
or in very sick diabetics to whom carbohydrates may not be given, — ■ 
alcohol may be given with advantage, and may materially lessen the 
results of carbohydrate hunger, such as acidaemia and acetonuria 
(N&ubauer) . 

Food and poison are not necessarily different things, for peptones 
and soaps when directly introduced into the blood are violent poisons. 
As, however, their chemical properties, their colloid nature, do not 
permit this, they are harmless food-stuffs when properly administered. 
If alcohol were to reach in proper amounts only the right place for its 
transformation, it would perhaps be quite as harmless as the higher 
alcohols, such as glycerin. Alcohol, however, differs from all such 
relatively harmless substances in its power of entering into solution 
with the lipoids. This property causes it to penetrate alike into all 
cells and to cause in them at least temporary disturbances of function. 
That this may lead to permanent serious results, especially to de- 
generative changes, is well known. 

BIBLIOGRAPHY 

Chauveau: Compt. rend. Acad, des sciences, 1901, vol. 132, pp. 65, 110. 

Durig: Pniiger's Arch., 1900, vol. 113, p. 380. 

1 i<k, A.: Korr. f. Schw. A., 1896, No. 14, p. 445. 

I'rey: Mitt, aus klin. u. med. Inst. d. Schweiz, Serie 4, 1896, No. 1. 

Harden, A., and Maclean: Journ. of Physiol., 1911, vol. 42, p. 64. 

Hellsten, A. F.: Skand. Arch. Phys., 1907, vol. 19, p. 201. 

Joteyko: Trav. Solv., vol. 6, p. 431, 1904. 

Joteyko: Trav. Solv., vol. 6, p. 447, here lit. 

Kassowitz: Fortschr. d. Med., 1903, Nos. 4 and 27. 

Kassowitz: Therap. Monatsh., 1908, Nos. 6 and 7. 

Kochmami, M.. u. \Y. Hall: Pftiiger's Arch., 1909, vol. 127, p. 280. 

Landsberg: Ztschr. f. phys. Chemie, 1904, vol. 41. 

Neubauer, O.: Mtinehn. 'med. Woch., 1906, No. 17. 

Beach: Biochem. Ztschr., 1907, vol. 3, p. 326. 

Bcheffer: Arch. f. exp. Path. u. Pharra., 1900, vol. 44. 

Bchumburg: Dubois' Arch., 1896, p. 537. 

Bchumburg: l)i<- Milit.-iirztl. Ztg., August, 1896. 

Btoklasa: PhyBiol. Zentralbl., L902, \<.l. It;, p. 712, and 1903, vol. 17, p. 465. 

\.iv;is: Pfltiger'B Arch., 190!), vol. 128, ]). 398. 

Weiland: Deut. Arch. f. klin. Med., 1908, vol. 92, p. 223. 

TKSTieri.A!; KXTllACTK 

At the close <ii' this section ;i very remarkable action of those 
extracts should be mentioned. This was first noted by Brown 
SSquard and his collaborators, and has recently been carefully in- 
28 



434 PHARMACOLOGY OF THE MUSCLES 

vestigated by Zoth and Pregl. According to these latter authors, the 
subcutaneous injection of Sequardine (a glycerin extract of bulls' 
testicles obtainable from Perrottet & Cie., Geneva) causes an extra- 
ordinary increase of the effect of systematic muscular exercise. 

Daily injections for one week produced no effect on the muscular power as 
measured ergographically or otherwise, and daily exercises without injections 
were also without effect. Both together, however, caused a marked increase in 
the muscular power, showing itself in postponement of fatigue objectively and 
subjectively, as well as in an increase in the benefit resulting from pausing to 
rest. In Zoth's experiments, in which heavy dumb-bells were used daily and 
daily injections were administered, the increase amounted to 14-20 per cent, 
of the original performance after 8, 9, or 12 days, while without injections 
70 practice exercises during five weeks caused an increase of but 12 per cent. 
Exercise plus injections resulted quickly in attaining an increase of power 
which by exercise alone was not attainable. A distinct increase in the cir- 
cumference of the upper arm also accompanied the increase in muscular power. 

These extracts appear therefore to bring about a peculiar improve- 
ment in the assimilative processes of the muscle-cells. 

BIBLIOGRAPHY 
Zoth u. Pregl: Piiuger's Arch., 1896, vol. 62, here literature, and 1898, vol. 69. 



CHAPTER XIV 
PHARMACOLOGY OF THE BLOOD 

Under pathological influences the blood may undergo both quan- 
titative and qualitative alterations which demand not only dietetic 
but medicinal treatment. 

Effects of Infusions on the Blood Volume. — The most im- 
portant alteration of the blood volume, and one which often imperils 
life, is acute anaemia, a diminution of the blood volume resulting 
from hemorrhage or profuse diarrhoeas (cholera) and affecting the 
whole vascular system, or in case of " bleeding into the abdominal 
vessels" as occurs in paralysis of the splanchnics, affecting chiefly 
the vitally important vascular systems of the heart and central 
nervous system. In such cases, merely increasing the volume of the 
circulating fluid by diluting the blood by intravenous — or in less 
urgent cases by subcutaneous [or rectal. — Tr.] — administration of 
physiological saline solution (0.9 per cent. NaCl) may be a life- 
saving measure. In such case the chief indication is to bring about 
more favorable conditions for the cardiac function (p. 319). In 
addition, according to Ott, the saline infusion actively stimulates 
the regeneration of the red cells. (See also Zachrisson.) 

A condensation of the blood may, on the other hand, be of 
value under certain conditions, as, for example, for the purpose of 
favoring the absorption of pleural or peritoneal exudates or of 
oedema. This may be accomplished by bringing about the loss of 
large amounts of water through the skin, kidneys, or intestine. (See 
discussions of diaphoresis, diuresis, and catharsis.) 

The most important anomalies of the blood are the alterations in 
the number and quality of the red and white cells which occur in 
chlorosis and other anaemias. In chlorosis the number of the red cells 
and their ha-moglobin content are markedly diminished. The indica- 
tion is, therefore, to bring about a greater production of normal 
healthy cells, for which indication iron has been for centuries con- 
sidered the most valuable drug. 

IRON 
Although originally the administration of iron in conditions of 
weakness, anaemia, and chlorosis was crudely empiric or else based 
on mystic ideas, it obtained ;i scientific foundation as early as 1746, 
when Mengh/ww discovered that iron was a characteristic constituent 
of the blond, existing " in sola sanguinis parte gldbulari." He also 
found that the administration of food containing iron increased the 
iron content of the blood. These observations, later confirmed by 

435 



436 



PHARMACOLOGY OF THE BLOOD 



numerous observers, were supplemented in 1830 by Fodisch, who 
found the iron content of the blood of chlorotics to be materially di- 
minished, and finally by Andral, Gavaret, and Delafond (1842), who 
demonstrated an increase in the number of the red cells after admin- 
istration of iron. These quantitative observations have since then 
been repeatedly confirmed. 

Older Theories as to Action of Iron. — From such observations it 
appeared that a scientifically founded and satisfactory theory for 
the effects of iron therapy had been obtained; that the iron which 
was administered was utilized in the formation of haemoglobin. 
However, before long the correctness of this view was seriously ques- 
tioned, chiefly for two reasons. Many clinicians cast doubt on the 
value of iron in the treatment of chlorosis, or assumed that the 
repeatedly demonstrated increase in the iron content, or in the 
haemoglobin or in the number of erythrocytes of blood, which followed 
the administration of iron, even Avhen other therapeutic procedures 
were not employed, was possibly not a real but only an apparent in- 
crease. As a matter of fact, up to this time the quantitative deter- 
minations of iron, haemoglobin, and red cells had been made only 
in a given unit of blood, and, therefore, any increase found might 
be only a relative one due to concentration of the blood. 



Red cells in mill- 
ions per cu. mm. 









1 










18 


kg. d 


og 


























s 




























1 
































-< 


















A 












7 




. 


\ 


















V 












T8 


9gm 


brec 


,1 










ff.ii 


7 gin. 


wati 










e 




































c 


i « 


S t 


>* / 


h /! 


i h Z 


h £k 


i* 






1 


A 


2 


h. 


J* 



Fia. 51. — Graphic representation of variation in the number of red cells'in the cu. 
mm. as a result of concentration and of dilution of the blood. 



Marked variations in the concentration of the blood actually do occur 
under various conditions, either as a result of furnishing water to the tissues, 
especially to the glands, or as a result of vasoconstriction. The effect on the 
concentration of the blood exerted by the digestion of dry food — i.e., by the 
pouring out of the digestive juices into the alimentary canal — is well shown 
by Buntzen's experiments on dogs (Fig. 51). Here feeding with bread in- 
creases the number of red cells in the unit volume by 10-20 per cent. In 
long-continued fasting also the relative number of red cells is markedly in- 
creased, for under these conditions the blood loses much more fluid from its 
plasma than from its cells (Fig. 52). This last observation has been con- 
firmed in human subjects by Andreesen. 

The effect of varying vascular tone is quite as well pronounced, with 
increased tone fluid passing from the blood to the tissues and the relative 
number of red cells rising, but falling with diminished tone. The vascular 
tone, as is well known, may be influenced through the vasomotor centres by 



IRON 



437 



various means. For example, it is diminished by alcohol (Fig. 53) and in- 
creased by the action of cold, — e.g., by cold baths ( Tonnissen ) . 

However, not every augmentation of arterial tone results in the passing 
out of plasma through the capillary ■wall, for, if the increased tone affects 
chiefly the smaller arteries and arterioles, the capillaries, being below the con- 
traction, contain but moderate amounts of blood under low pressure, and 
therefore need not squeeze any plasma into the tissues. If, however, the tonic 



Red cells in millions 
9 









/ 


'\ 




Dog 


of 9 


kg. 








/ 


- 




\ 


\ 












< 


' 








\ 


\ 










\ 


Inn 


nitio 


i 


















\ 












t/\ 










\ 












V 










\ 


\ 






4 
















\ 




i 




















V-. 


' 













9.0 kilo 
8.3 



Z 4 6 8 10 12 14 16. 18 20 Tag 

Fig. 52. — Influence of fasting on tne concentration of the blood. 

contraction affects principally the most peripheral capillaries or a portion of 
them (epinephrin intravenously), the blood stagnates in the less-contracted 
portions of the capillaries and arterioles lying above the constriction, 
and is there subjected to a high pressure which squeezes out the plasma fluid. 
in a similar fashion plasma is expressed in large quantities in artificial plethora, 
such as results from infusion of blood, although the vessels are not constricted. 
Magnus found that from 20 to 40 per cent, of the infused fluid was expressed 



Red cells 
in millions 

8 




j 


!., 


ll In 


m 


in 












of 


UU 


kg. 








tL 71 




alt 


oh 


ol 




7 




















\ 












/ 


6 








-— 


y 










\ 


/ 































Red cells, in millions 



u 


an 


</. 


',2 


























1 














> 


£ 


/ 


\ 


J 

i 


r, 


7 


a 


a 1 


> / 



»"/0" 



e*/&*M 



250 c.c. wine 
daily 



daily 



Fig. 53. — Influence of alcohol on concentration of blood (Avdrcesen). 

into the tissues 3-5 minutes after infusion of homogeneous blood in amounts 
oorresponding to 20-50 per cent, of their original blood volume. In such cases 
the; blood was correspondingly concentrated. 

One might be tempted to explain the variations in the relative number of 
blood-cells as being duo not to a passing in and out of plasma through the walls 
of the finest capillaries, hut by assuming an emigration of cells back and forth 
from reserves of concentrated blood, perhaps from tho wide mesenteric veins, 
so that these variations would be explained as due only to an alteration in 
the distribution of blood containing varying numbers of red cells. 

However, there are no grounds for assuming the existence of reserves of 
blood-cells, for the concentration of the red cells is almost equal in all veins and 
arteries [Hess, Erb, Donath) . 



438 PHARMACOLOGY OF THE BLOOD 

These variations, however, which depend on administration of food or loss 
of water are not lasting, and cannot in any way explain the constant increase 
in the number of erythrocytes which results from the successful treatment of 
chlorosis. 

Another series of objections to the view that iron medicinally 
administered is utilized for the formation of hemoglobin base them- 
selves on the physiology and toxicology of iron. 

Iron in Pood-stuffs. — In all food-stuffs, vegetable as well as 
animal, iron is present in assimilable form and in amounts sufficient to 
supply the increasing needs of the growing body and to compensate 
for the amounts lost by adult animals in the faeces and urine. It is 
present in these food-stuffs not in the form of salts, in winch it 
may be directly demonstrated by ordinary reagents, but in organic 
combinations, probably in combination with nucleoproteids or similar 
substances. In this form the iron is without doubt absorbed and pro- 
vides the body with the material for the formation and maintenance 
of its ferruginous constituents. With the exception of milk, rice, 
white bread, and many fruits, the substances used as food contain iron 
in such quantity that an ordinary mixed diet supplies enough iron 
for ordinary needs. 

Iron Balance during Administration of Inorganic Iron. — If this 
be so, why not give anaemic cases an ample diet of food which is rich 
in iron, in place of administering iron salts, of which, to begin with, 
it was not known whether they were absorbed at all or, if absorbed, 
in what amounts? Formerly, in fact, it appeared very doubtful 
whether iron salts were absorbed at all, for in the human urine under 
normal conditions 1-2 mg. of iron are excreted daily, and after the 
administration of iron salts this amount is not increased, although in 
the case of almost all substances, which are absorbed and reach the 
circulation, at least a part is excreted in the urine {Gottlieb). As a 
matter of fact, almost all the iron thus administered may be re- 
covered from the faeces {Marfori, Kletzinski, Hamburger). 

This fact, however, was not a valid argument against the absorba- 
bility of iron combinations, for Wild's exact quantitative determina- 
tions of the iron content of different portions of the intestine have 
demonstrated that, of the iron contained in food which is certainly 
absorbed, any superfluous amount is excreted again in the lower 
bowel. Moreover, ordinary salts of iron when administered sub- 
cutaneously are excreted not by the kidneys, but exclusively by the 
intestine, as has been shown by Gottlieb. As the bile contains only 
traces of iron (Novi), this excretion must be the work of the intestinal 
glands. In view of these facts, it was not possible to deny that, when 
salts of iron were administered, they were absorbed in the upper 
portion and after circulating in the body were excreted in the lower 
portion of the intestine. 

Finally, still another objection was raised by those doubting the 
value of iron medication, on the ground that, if corrosive effects be 



IRON 439 

excluded, neither chronic nor acute poisoning followed the oral ad- 
ministration of iron, although iron salts when administered sub- 
cutaneously or intravenously had proven themselves extremely toxic, 
similarly to arsenic {Meyer and Williams). 

It was, therefore, concluded that, as ordinary food-stuffs contain 
sufficient iron, and as the medicinal preparations of iron are probably 
not absorbed and therefore cannot be utilized, the favorable effects 
of the administration of these preparations must be explained by 
local action in the alimentary tract, especially by a protection of the 
iron in the food from alteration by substances present in the bowel 
which have a strong affinity for iron, such, for example, as the 
sulphides. 

These conclusions have, however, all been shown to be incorrect. 
The lack of toxicity of iron administered by mouth in no way in- 
dicates that it is not absorbed, for many substances, — e.g., potassium 
salts, curare, and others, — although extremely toxic when administered 
intravenously or subcutaneously, are absorbed in large amounts from 
the intestine without producing any toxic effects. This is in many 
cases due to a protective influence of the liver, which is the first organ 
reached by these substances after they are absorbed, and which either 
renders them harmless by chemical means, or retains them for a 
time (Rothberger) , so that their excretion by the kidney or intestine 
keeps pace with their arrival in the blood and thus prevents the 
attainment of that concentration in the blood necessary to cause 
toxic effects. This is also the case with the salts of iron. 

Proofs of the Absorption of Inorganic Iron Salts. — In ad- 
dition, it has been definitely proven that inorganic salts of iron may 
be absorbed in the absence of any lesions of the intestinal mucous 
membrane. That this occurs chiefly in the small intestine has been 
demonstrated both by microchemical examination of the intestinal 
mucous membrane (MacCallum, Quincke, Gaule) as also by the 
chemical demonstration of the presence of iron in the lymph from 
the thoracic duet 45 minutes after the introduction into the stomach 
of a 0.06 per cent, solution of ferric chloride (Gaule), and also by 
comparison of the amounts of iron administered to men and animals 
and the exactly determined amounts excreted by the intestine and 
the kidney (Ilofmann). 

Its Utilization in the Formation of Haemoglobin. — Finally, 
Kwnh I has shown that iron salts are not only absorbed, but that they 
are stored up in the body for future use and are used in the synthesis 
of hsemoglobin. This ;mthor repeatedly bled two puppies as nearly 
alike as possible and thus rendered them amemic and impoverished in 
iron, feeding both animals exclusively on milk, which contains very 
little iron, except thai one of the subjects received daily about 6 mg 
of Pe in the form of Liq. ferri albmninati. Aiter six weeks one dog 
was extremely aneemic, its blood containing only 0.010 per cent. 



440 



PHARMACOLOGY OF THE BLOOD 



Fe 2 3 , and the whole liver only 0.004 gm. Fe 2 3 , while the other dog, 
which had received the iron, was of normal strength, its blood contain- 
ing 0.035 per cent. Fe 2 3 and the liver 0.032 gm. Fe 2 3 . 

These results were confirmed by Cloetta in nine young puppies, 
which were subjected to experiment immediately after weaning. All 
of them received no food except milk, but six received in addition 
daily doses of 35 mg. of iron, as lactate of iron or as ferratin, a 
proteid containing iron in combination. The haemoglobin was esti- 
mated at various intervals, with the results given in the table below. 
Haemoglobin in Growing Puppies Fed on Milk. 











Group II, milk and 


Group III, milk 


Hgb. expressed in 


Grour. 


I, milk alone 


lactate of iron, 


35 mg. 


and ferratin, 35 mg. 


percentages of normal 








Fe daily 




Fe daily 


Hgb. content 
















1 


2 


3 


1 


2 


3 


1 


2 


3 


After 4 weeks. . . . 


78 


81 


51 


95 


97 


94 


96 


94 


94 


After 7 weeks. . . . 


66 


67 


31 


92 


95 


93 


95 


93 


91 


After 9 weeks. . . . 


45 


40 


28 


87 


94 


95 


98 


94 


90 


After 12 weeks. . . . 


35 




24 




99 


94 


99 




93 



Kunkel's results have been completely confirmed by Abderhalden 
working in Bungs' s laboratory. In a large series of parallel observa- 
tions, Abderhalden fed to young puppies as soon as weaned and to 
new-born guinea-pigs normal diet, or a diet containing little iron, and 
both of these diets with or without addition of iron, using in some 
cases salts of iron, and in others organic iron preparations such as 
hasmatin or similar substances. He found that all the iron prepara- 
tions, when added to the diet containing little iron, were absorbed 
and used for the formation of haemoglobin. When, however, iron 
preparations were added to the normal diet which contained iron, 
remarkable difference was noted between the animals which had 
received inorganic iron and those which had received organic iron. 
In the latter group no recognizable differences from the normal con- 
trols were noted, but the addition of inorganic iron preparations to 
the normal diet markedly stimulated both the formation of haemoglobin 
and the gain in weight. These effects, however, were produced only 
for a certain length of time, after which habituation appeared to 
develop. 

By these experiments, which have been substantially confirmed 
elsewhere (Tartakowsky) , it may be considered as proven that the 
salts of iron may not only be utilized as material for the synthesis 
of haemoglobin, but may also exert a specific action on the blood- 
forming organs (bone -marrow) and probably on the processes of 
growth and metabolism in other tissues. This latter is indicated by 
Romberg's observation, that in chlorosis the tissues contain abnormally 
large amounts of water and that this disappears under the influence 
of iron. 



IRON 441 

Finally, the histological findings in the bone-marrow agree "with 
this assumption of a stimulation of the blood-forming organs by iron. 
According to Fr. Midler, the bone-marrow of animals artificially 
rendered anaemic contains more nucleated red cells when iron is ad- 
ministered than is the case when no iron is added to the normal diet. 

It must therefore be assumed that the effects of iron in chlorosis 
are due to two factors : first, the utilization of the iron in the synthesis 
of haemoglobin and in the formation of reserve substances which are 
rich in iron and are stored up in the liver; and, second, a specific 
stimulation of the cells which form haemoglobin, as taught by Trous- 
seau and as reaffirmed by Harnack and v. Noorden. 

Relative Inefficiency of Organic Iron Preparations. — On account 
of the difficulty with which they are decomposed, haemoglobin deriva- 
tives produce this second specific and therapeutically very important 
effect either not at all or in only a slight degree. Apparently they 
appear to be utilized only in the same way as the organic iron 
present in food-stuffs. [The same, in all probability, holds true for 
all of the high-priced and much-advertised preparations containing 
iron in organic combination. Although their vendors claim for them 
extraordinary therapeutic powers, they are without exception in all 
probability less effective than the old simple inorganic preparations. 
The only justifiable claim which may be made for them is that they 
do not produce the same local effects on the mucous membrane as do 
some of the inorganic preparations. This advantage is, however, 
purchased at the cost of therapeutic efficiency. — Tr.] 

This power possessed by iron, of stimulating or causing metabolism 
and growth, is only a specific instance of its general importance for 
all vital processes. It is a constant and integral constituent not only 
of the lower animals (Crustaceae, etc.), where it is present as ferrin, 
but it is necessary for the growth of the fungi (Molisch) and of the 
higher plants, in which latter it is necessary for the production of 
chlorophyll, although this contains no iron. 

As exact experimentation and clinical experience both indicate 
that the action of the iron salts is materially different — at the least 
is quantitatively different — from that of the iron contained in food- 
stuffs, a rational foundation has been gained for the administration 
of iron in chlorosis in addition to providing for a diet rich in iron. 

Moreover, the ordinary diet of man is by no means very rich in 
iron. Stockman's figures are as follows: Ordinary diet 8-11 mg. per 
diem; insufficient diets, especially when appetite is poor, 6-8 mg., 
and at times as low as 4 mg. In the daily output of faeces and urine 
of four exactly observed cases, he found that the iron approximately 
equalled the amount ingested. During fasting an adult man excretes 
8-10 mg. of iron, for the celebrated faster Cctti the mean figure for 
the iron in the faeces was 7 mg., and for Brcithaupt 8 mg. According 
to these figures, the norma] human diet contains enough iron to replace 



442 PHARMACOLOGY OF THE BLOOD 

the unavoidable loss through, wear and tear, but hardly enough to 
overcome any deficiency resulting from an existing disease. The im- 
portance of these facts is self-evident. 

Comparative Value of the Different Iron Preparations. — 
From what has gone before, it may be concluded that, for purposes 
of practice, all iron preparations are in principle of equal value, 
with the exception of haemoglobin, its derivatives, and similar organic 
combinations which in their behavior appear to resemble the iron 
contained in food. This has been confirmed by clinical experiments 
conducted for the purpose of investigating this assumption. 

Behavior in the Alimentary Canal. — However, the different prep- 
arations differ quite materially in respect to their local actions on 
the mucous membrane of the alimentary canal and the rapidity and 
completeness with which they are absorbed. All the simple salts of 
iron, which possess an acid reaction, exert an astringent or corrosive 
action on mucous membranes, which varies in its intensity with the 
amount and the concentration. If the stomach be especially suscep- 
tible, this may be the cause of digestive disturbances or loss of ap- 
petite, and especially of constipation. Examples of such preparations 
are Ferrum reductum, converted into the chloride by the gastric 
juice, Ferri carbonas saccharatus, and the lactate, citrate, and malate 
of iron. By addition of alkali the acid reaction of the iron salts 
and their astringency are lessened. This accounts for the fact that 
such preparations as Blaud's pills are usually so well borne. The 
same is true of the chalybeate waters, which usually contain alkaline 
carbonates. Their great dilution also renders their local action prac- 
tically negligible. Preparations containing iron in colloidal form 
or in combination with proteid, from which it is split off only gradu- 
ally, are still less likely to produce undesirable local effects. Dialyzed 
iron and the albuminate or peptonate of iron are examples of such 
preparations. 

Organic Iron Preparations. — Ferratin (acid albuminate of iron) 
containing 3 per cent. Fe, carniferrin ( phosphocarnate of iron) 20 
per cent. Fe, and triferrin (paranucleinate of iron) 30 per cent. Fe, 
all contain their iron in very firm combination, and, like the various 
commercial preparations, which contain ha?matin, produce no local 
effects, but also do not exert a specific stimulant effect after ab- 
sorption. 

In any iron preparations, ionizable iron gives with hematoxylin a dark- 
violet color-reaction. This may be used for determining whether or not the iron 
be present in available form (Macallum). 

Ferric chloride is not only an astringent and irritant but also 
a coagulant for blood and possesses slight antiseptic powers. 

Toxicology. — Actual poisoning by iron can occur only when iron 
salts are administered parenterally, — i.e., subcutaneously or intraven- 
ously. 



MANGANESE AND ARSENIC 443 

In rabbits, dogs, and cats, 30 nig. per kilo, body weight when thus ad- 
ministered cause paralysis and death. If the amount administered is so large 
that not all the iron can combine with the proteids of the blood, the free iron 
salts damage the kidney epithelium and are excreted by this organ, but such 
harmful effects never result from the subcutaneous administration of iron, some- 
times employed in therapeusis {Quincke, Lepine). [One occasionally meets 
with statements that iron may in this way be harmful in cases of nephritis, but 
this view is in absolute contradiction to both experimental and clinical evi- 
dence. — Tr.] 

BIBLIOGRAPHY 

Abderhalden: Ztschr. f. Biologie, 1900, vol. 39. 
Andreesen: Diss., Dorpat, 1S83. 

Buntzen: Om Ernaringen og Blodtabets, etc., Kjobenhavn, 1879. 
Cloetta: Arch. f. exp. Path. u. Pharm., 1897, vol. 38. 
Erb: Deut. Arch. f. klin. Med., 1907, vol. 88, p. 36. 
Gaule: D. med. Woch., 1896, vol. 22, Nbs. 19 and 24. 
Gottlieb: Arch. f. exp. Path. u. Pharm., vol. 26. 
Gottlieb: Zeitschr. f. physiol. Chem., 1891, vol. 15. 
Hamburger: Zeitschr. f. physiol. Chem., 1878, vol. 2; 1880, vol. 4. 
Harnack: Lehrb., 1SS3, p. 459. 

Hess: Deutsch. Arch. f. klin. Med., 1903, vol. 79, p. 128. 
Hofmann: Virchow's Arch., 1898, vol. 151. 
Kletzinski: Z. Ges. d. Aerzte, Wien., 1854, vol. 10, p. 2. 
Kunkel: Piiiiger's Arch., 1895, vol. 61. 
Lepine: Sem. med., 1897, vol. 17, p. 25. 
Macallum: Journ. of Phys., 1894, vol. 16; 1897. 
Magnus: Arch. f. exp. Path. u. Pharm., 1901, vol. 45, p. 210. 
Marfori: Arch. f. exp. Path. u. Pharm., 1892, vol. 29. 
Meyer u. Williams: Arch. f. exp. Path. u. Pharm., 1881, vol. 13. 
Molisch: Ber. Wien. Akad. Wiss., 1894, vol. 103. 
Miiller, Fr.: Virchow's Arch., 1901, vol. 164. 
Noorden: Berl. klin. Woch., 1895. 
Novi: Ann. di chim. e di farm., 1890, vol. 9. 
Ott: Virchow's Arch., 1883, vol. 93, p. 114. 
ntiincko: Arch. f. exp. Path. u. Pharm., 1896, vol. 37. 
Romberg: Berl. klin. Woch., 1897, No. 25. 

Rothberger u. Winterberg: Arch, intern, de Pharmacodynamic, 1905, here litera- 
ture. 
Stockman: Journal of Phys., vol. 18, p. 484, 1895. 
Tartakowsky: Piiiiger's Arch., 1904, vols. 101 and 102. 
Tonnissen: Diss., Erlangen, 1881. 

Trousseau: (Unique medic, Paris, 1868, vol. 3, p. 515. 
Virchow's Arch., 1893, vol. 131, Suppl. 
Zaclirisson, F. : Lpsala Liik. Ferh. N. F., 1900, vol. 5, p. 179. 

MANGANESE 
Nothing certain is known concerning the influence on the hlood 
exerted by this metal, but Hannon* claimed to have cured certain 
cases of chlorosis by its use, while other authors, among them 
Cervello, have made similar claims for lead and for copper. 

BIBLIOGRAPHY 

Cervello e Bambini : Su] potere omatogcno dei mctalli pesanti, Palermo, 1894. 

ARSENIC 

It appears to he well established that arsenic exerts an action, 
wry similar to that of iron, on the hematopoietic organs. This is 

* Tlan-non attributed the good effects obtained by this drug to its power 
of protecting the Food iron from the sulphideB presenl in the intestine. 



444 



PHARMACOLOGY OF THE BLOOD 



indicated not only by clinical evidence, but also by Bettmann's and 
Stockmann's findings in the bone-marrow of animals treated with 
arsenic. Thus far there is no scientific foundation for the use of 
arsenic in pernicious anaemia, leukaemia, and pseudoleukemia. 



HIGH ALTITUDES 

A limitation of the oxygen supply affects the haematopoietic organs 
much as does iron or arsenic. It is well known that . hemorrhage is 
followed by marked activity of the functions of the bone-marrow and 
by rapid regeneration of the blood. In fact, bloodletting has been em- 
ployed in chlorosis as a means of exciting an apparently sluggish bone- 
marrow to greater activity. This, however, can be accomplished in 
a less harmful manner by cutting down the oxygen in the inspired 
air. 

As early as 1877, Paul Bert expressed the opinion that in high 
altitudes the number of the red cells and the haemoglobin must be 
increased in human beings or animals in order to make it possible 
for them to obtain sufficient oxygen from the rarefied air. Viault 
in 1890 confirmed this view completely by observations made on him- 
self and a companion during a three weeks' stay at an altitude of 
over 4000 metres. He found the red cells increased from 5 to 7% or 8 
million per cu. mm. Analogous observations have since then been 
made by numerous others, especially by Egger and by Miescher and his 
pupils (see Fig. 51) . 

Further investigations have shown that this result is due to the 
diminution of the oxygen in the air, for the same increase in the 
number of the erythrocytes results from long-continued breathing of 
rarefied air (Sckaumann) , or air from which part of the oxygen has 
been removed (Sellier). 

For a time it was uncertain whether this increase of the red cells 
was relative or absolute, — i.e., whether the blood on account of loss 
of plasma appeared to contain more cells or whether the amount of 



Author 


. . , Height 
Annnal , in ^ 


Hsemogl. 
per kg. 


Air 
diluted to 
correspond 
with alti- 
tude of — - 


Hsemogl. 
per kg. 


Diff. in 
per cent. 


Jaquet u. Suter 


Rabbit 

Rabbit 

Rabbit 

Rat 


280 
280 
280 
280 


5.39 
5.50 
7.99 
8.92 
10.78 


1800 m. 
1600 m. 
1800 m. 
1800 m. 
2150 m. 


6.59 

6.73 
9.32 
10.62 
13.00 


+23.0 
+20.0 


Abderhalden 


+ 16.6 
+ 19.0 




Dog 


+20.0 











plasma remained constant while abnormally large numbers of red 
cells were produced. This was settled by determining the total 
haemoglobin content of animals which had been kept in atmospheres 
containing different amounts of oxygen, due allowance being made for 



HIGH ALTITUDES 



445 



Red cells . 


^___ y 




y \ 




1 S Rabbit \ 




/ \ 




/ \ 




/ ^^ 




/ N. 




• 1/ \ 




s^, / \ 




\ 




Ba.se! 


_g* 




*- t 


26Gm \ 




• 






l 


I • |" 



£ weeks 




4 g weeks 




O S ,;.,■,/.-;, 

Fro. 54.— Effect of various altitudes on the number of the erythrocytes. 



446 PHARMACOLOGY OF THE BLOOD 

variations in body weight. The results of such investigation as shown 
in the preceding figures demonstrate with certainty an actual increase 
in the number of the red cells. This is also indicated by the his- 
tological examination of the blood and bone-marrow of the animals 
kept at high altitudes, which demonstrate the presence of numerous 
normoblasts in the blood, and by the redness of the bone-marrow. 

Recently Douglas, using Haldancs method for determining the total haemo- 
globin, questions these conclusions, but this method, according to Dreyer and 
Ray, is not reliable, and therefore his objections cannot be considered as proven. 

This increased production of blood-cells and haemoglobin under 
the influence of diminished oxygen tension, — i.e., of very slightly de- 
ficient supply of oxygen — is to be considered as an unusually delicate 
compensatory and regulative reaction of the haemoglobin-producing 
organs, especially the bone-marrow. 

This new formation of red cells is, however, not demonstrable until 
the rarefied air has been acting on the subject for several days, but 
the number of cells to the cu. mm. is at once distinctly increased, as 
a result of a temporary concentration of the blood in the cutaneous 
vessels, due probably to an alteration in the distribution of the blood 
throughout the body. 

BIBLIOGRAPHY 

Bert, Paul : Sur la pression barometrique. 

Boycott and Douglas: Journ. Path, and Bacter., 1909, vol. 13, p. 256. 

Douglas, Gordon: Journ. of Physiol., 1910, vol. 40, p. 471. 

Dreyer and Ray: Phil. Transact. R. Soc, London, 1910, vol. 201, p. 133, ser. B. 

Egger, Miescher u. s. Schuler: Korr. f. schweiz, Aerzte, 1893, No. 24. 

Grehant et Quinquaud: J. d. l'anat. et phys., 1882, vol. 18, p. 5G4. 

Jaquet: Ueber d. physiol. Wirkung d. Hohenklimas, Basel, 1904, literature. 

Schaumann u. Rosenquist: Z. f. klin. Med., 1898, vol. 35. 

Sellier: These, Bordeaux, 1895. 

Zuntz, Loewi: Miiller u. Gaspari, 1906, p. 197. 

Polycythaemia, or erythrocythaemia, is a condition practically 
the opposite to chlorosis and one due to unknown causes. As far as is 
known, pharmacological agents exert no influence upon it, but re- 
peated bloodlettings at times give passing subjective and objective 

relief. 

BIBLIOGRAPHY 

Border: Med. Klinik, 1911, vol. 5, p. 301, literature. 

LEUCOCYTES 
Up to the present time, there is no satisfactory explanation of the 
manner in w T hich pharmacological agents influence the leucocytes. 
While the number of these cells present in the blood at the surface 
of the body may be influenced by the distribution of the blood in 
different parts of the body (Bolilandt), increased formation or an 
increased emigration into the blood from the organs in which they 
are formed may cause an increase in their number. Thus, the leuco- 
cytosis caused by pilocarpine is the result of the contraction of the 



LEUCOCYTES 447 

smooth muscles in the spleen and the lymphatic glands squeezing 
lymphocytes into the blood, for after ligature of the splenic vessels 
this drug does not alter the number of the leucocytes (Harvey). 
Action on the lymphatic elements of the intestine is the probable 
cause of the leucocytosis appearing during the increased activity and 
hyperemia during digestion, as also for that caused by bitters and 
other numerous drugs which stimulate or irritate the alimentary 
mucous membrane (Polil). 

Quinine and salicylic acid both possess a specific action on the 
leucocytes, their movements being inhibited even by very dilute solu- 
tions, "while concentrated solutions kill them (Binz). 

The distribution of the leucocytes throughout the circulation is 
influenced by chemotactic substances, and their number may be 
affected in an indirect manner by numerous drugs. Thus, the applica- 
tion of irritants to the skin is followed at first by hypoleucocytosis, 
later by hyperleucocytosis (Winternitz). According to Hamburger 
and de Haan, lime salts specifically augment the motility and phago- 
cytic power of the leucocytes. 

Finally, the leucocytes may be destroyed in the circulating blood, 
for they are labile elements prone to destruction and succumb to the 
action of many destructive factors (see Metabolism). Thus, they 
are destroyed by X-rays, and in leukaemia the spleen diminishes in 
size (Linser). [Benzol has recently been shown to greatly diminish 
the number of leucocytes in leukaemia. — Tr.] 

On the other hand, the destruction of the red cells by specific 
poisons is accompanied by a hyperleucocytosis, due both to increased 
production of the white cells and to their being swept into the blood 
from the tissues (Heinz). 

BIBLIOGRAPHY 
Binz: Das Chinin, Berlin, 1875. 
Bohlandt: Zbl. f. inn. Med., 1899. 
de Haan: Biochem. Zeitg., 1910, vol. 24, p. 470. 
Ha>vey: dourn. of Phys., 1900, vol. 35. 

Heinz: llandb. d. oxp. Path. u. Therap., 1905, vol. 1, p. 450. 
Lillfler u. Helber: D. Arch. f. klin. Med., 1905, vol. 83. 
Pohl: Arch. f. exp. Path. u. Pharm., 1889, vol. 25. 
Winternitz: Arch. f. exp. Path. u. Pharm., 189G, vol. 3G. 

COAGULABILITY 

Among the changes which take place in the unformed elements of 
the blood, its coagulability is one which may be influenced by pharma- 
cological agents, — e.g., in obstinate bleeding, purpura hemorrhagica, 
haemophilia ( ?). 

According to practical experiences, the administration of lime salts 
favors the formation of firm clots,* while Reverdin claims similar ef- 

* [Doubt lias been thrown upon this claim by dole and others who have failed 
to note that Buch increase in the coagulability of the blood followed the adminis- 
tration of lime in v.niuiis forms or that of gelatine. There is also a difference of 
opinion among clinicians as to this matter, which certainly needs further investi- 
gation. — Tr.] 



448 PHARMACOLOGY OF THE BLOOD 

f ects from Glauber 's salt by mouth or intravenously, and v. d. Velden 
claims the same results for large injections of NaCl solutions. Gelatin 
(15-20 gm. daily) internally or subcutaneously is stated to stop or 
lessen capillary bleeding (A. Bass). This may be done only to the 
lime which is present in the gelatin in the amount of 0.6 per cent. 
(Zibcll). [It should not be forgotten that cases of tetanus have been 
caused by the injection of insufficiently sterilized solutions. — Tr.] 

[Epinephrin, when injected intravenously or subcutaneously into 
experimental animals, often causes an annoying increase in the coagu- 
lability of the blood. It is possible that this also occurs in man, 
and it may be that the favorable effects claimed from the use of 
this drug in hemorrhage from inaccessible points is due to such 
action. — Tr.] 

The diminution or abolition of the coagulability of the blood 
will probably never be therapeutically indicated unless to prevent 
threatening or progressive venous thrombosis, but in many ex- 
periments in animals such action may be desirable. 

Sodium oxalate or citrate (1 to 100), when added to the blood, by combining 
with its calcium prevents coagulation. However, these salts (or the depriva- 
tion of calcium) are toxic for the heart and the nervous system, and therefore 
they cannot be used in living animals, but only in experiments where surviving 
organs are perfused. [Here, too, their value is very doubtful. — Tb.] On the other 
hand, the glands of the leech contain a substance which is harmless when in- 
jected and which for a time prevents coagulation (Haycraft). Franz and 
Jacoby have named this substance hirudin. In the purest form in which they 
were able to obtain it, it appeared to be deutero-albumose. One milligramme 
of it will permanently prevent the coagulation of 20 c.c. of rabbit's blood. 

BIBLIOGRAPHY 

Bass, A.: Zbl. f. d. Grenzgeb. d. Med. u. Chir., 1900, No. 6. 
Franz u. Jacoby: Arch. f. exp. Path. u. Pharm., 1903, vol. 49. 
Haycraft: Arch. f. exp. Path. u. Pharm., 1884, vol. 18. 
Kaposi: Mitt a. d. Grenzgeb. d. Med. u. Chir., 1904, vol. 13. 
Reverdin: Rev. med. de la Suisse rom., 1895, p. 506. 
v. d. Velden: Verh. Kongr. inn. Med., 1909, p. 155. 
v. d. Velden: Deut. med. Woch., 1909, No. 5. 
Zibell: Miinchn. med. Woch., 1901, No. 42. 

VISCOSITY 

In recent years considerable attention has been paid to the vis- 
cosity, — i.e., to the internal friction — of the blood in physiological 
and pathological conditions {Kramer) , and attempts have been made 
to find drugs or other agents which will lessen the viscosity and thus 
facilitate the circulation of the blood. 

As first claimed by Poiseuille and confirmed by Muller and Inada 
and by Kottmann, potassium iodide appears to produce this effect, and 
recently there is a tendency to attribute to such action the beneficial 
effects which follow the use of this drug in arteriosclerosis.* The 
diminished viscosity resulting from the administration of this drug 
is not due to any alteration of the plasma, but is probably the result 

* [See J. of A. M. A., 1912, for resume of the literature. — Tr.] 



TOXICOLOGY OF THE BLOOD 449 

of alteration of the red cells. Mere changes in the volume of the red 
cells markedly influence the viscosity of the blood, so that the intro- 
duction of CO, into the blood, which augments the volume of these 
cells, markedly increases the viscosity. For this reason in asphyxia 
the viscosity of the blood is much increased. [The practical impor- 
tance of this effect of CO, in increasing the viscosity of the blood has 
not been sufficiently appreciated by the general medical profession. 
In eases with even moderate cyanosis, marked relief may be given 
to a struggling heart by any measures which will relieve this con- 
dition. In view of the general skepticism as to the value of oxygen 
inhalations, these facts should not be forgotten. — Tr.] 

BIBLIOGRAPHY 

Hirsch u. Beck: Arch. f. klin. Med.. 1901. vol. 69. 

Kottmann: Korr. f. schweiz. Aerzte, 1907, here literature. 

Kramer: Bestimmungsmethoden, Messung d. Durchflusszeit durch ein Capillar- 

rohr. 
Mtiller u. Inada: Deut. med. Woch., 1904. 
Poiseuille: Ann. de chir. et de phys., 1S43. 

Alterations in the Chemical Composition of the Plasma. — 
Under certain conditions it may be desirable to bring about an altera- 
tion of the inorganic elements of the plasma, — that is, to introduce 
certain salts which appear to be lacking. In these cases, however, the 
alteration or pathological composition is not confined to the blood 
alone, but affects all the tissue fluids and to some degree the tissues 
themselves, including the red cells, in so far as the ions in question 
are able to permeate them. An example of such procedure is perhaps 
to be found in the administration to scorbutic patients of the salts of 
the vegetable acids and potassium, but this therapy rests on a mere 
assumption for which there is no real scientific basis. There is no 
doubt, however, that such is the explanation of the benefits resulting 
from the addition of NaCl to diets composed entirely or chiefly of 
vegetable food, for with such diet large amounts of potassium salts 
pass Ihrough the body and, by mass action, compel the excretion of its 
sodium salts (Bunge). (See Salt Action, p. 388.) 

Alkalinity. — In conclusion, mention should be made of dimin- 
ished alkalinity of the blood, a very important condition and one 
often amenable to therapeutic measures. Evidently it is always 
merely one expression or symptom of a general metabolic disturbance, 
in which abnormal amounts of acids (lactic acid, oxybutyric acid, and 
others) accumulate in the body. (See Pharm. of Metabolism, p. 389.) 

TOXICOLOGY OF THE BLOOD 
In addition to the various therapeutically useful agencies by 
which the composition of the blood may be influenced, there are a 
number of others which are always harmful and may thus be termed 
blood poisons. Of these the more important will be considered. 
29 



450 PHARMACOLOGY OF THE BLOOD 

CO, carbon monoxide, the chief poisonous constituent of coal-gas 
and illuminating gas, has an affinity for ha?moglobin about 200 times 
as strong as has oxygen. Therefore, when present in the atmos- 
phere in a concentration only 1/200 of that of oxygen, — i.e., in a pro- 
portion of 1 to 1000 by volume, — it is able to replace one-half of the 
oxygen in the haemoglobin, and in higher concentrations to replace 
it almost entirely. 

By use of the following equation, it is possible to calculate the extent to 
which a given amount of CO will replace the oxygen in blood at body tem- 
perature (Hiifner), 

100 

x 

If Vo = percentage of 2 in the air and Ye = percentage of CO, then a? = the 
percentage of the haemoglobin which will combine with CO. 

If, for example, the air contains 21 per cent. 2 and 0.1 per cent. CO, 

100 10 ° „ooi 

2^688 = 42.21 percent. 

i.e., under these conditions nearly one-half of the blood would be saturated with 
CO if the subject remained in such an atmosphere sufficiently long. 

If the air contain 0.3 per cent. CO, x — 68.7 per cent., and human 
beings cannot survive such conditions, for in them death results when 
60-70 per cent, of their haemoglobin is saturated with CO. In birds, 
with their higher temperature, 50-60 per cent. CO saturation of the 
blood is fatal, but rabbits survive up to nearly 80-90 per cent. {Dreser, 
Hiifner). If the supply of CO ceases (before death ensues), or, other- 
wise expressed, if its concentration in the air sinks to zero, it is 
gradually driven out from the blood by the pure air breathed in, and 
the larger the amounts of oxygen in the air the more rapidly does 
this occur. The recovery from poisoning by carbon monoxide is, there- 
fore, materially accelerated when pure oxygen is inhaled. [Direct 
arm-to-arm transfusion of blood is also doubtless a life-saving pro- 
cedure in such cases, and in extremely grave cases should, when 
feasible, be employed. — Tr.] 

BIBLIOGRAPHY 

Dreser: Arch. f. exp. Path. u. Pharm., 1891, vol. 29. 
Hiifner: Journ. f. prakt. Chem., 1884, vol. 30, p. 68. 
Hiifner: Arch. f. exp. Path. u. Pharm., 1902, vol. 48. 

Hydrocyanic Acid. — In poisoning by this acid, which kills by 
rapid paralysis of the respiratory centre, the blood also is affected, 
the absorption of oxygen by the oxidizable elements of the body cells 
being interfered with or prevented, just as other so-called catalytic 
processes are inhibited by HCX (Gaehtgens, Geppert). For this 
reason, the venous blood has almost the same color and 2 
content as arterial blood. Metha?moglobin resulting from decompo- 



TOXICOLOGY OF THE BLOOD 451 

sition or other processes forms with cyanides a bright red combination, 
cyanhaemoglobin, which at times renders possible the recognition oi 
cyanides as the cause of death (Robert, v. Zeynek). 

BIBLIOGRAPHY 

Gaehtgens: Med.-ckem. Untersuch., Berlin, 186S, No. 3. 
Geppert: Ztschr. f. klin. Med., 1889, vol. 15. 
Kobert: Ueber Cyanniethamoglobin, 1881. 
v. Zeynek: Ztschr. f. physiol. Chem., 1901, vol. 33. 

JMeth^emoglobin is formed from oxyhemoglobin by the action 
of a large number of substances. This is a combination of oxygen and 
haemoglobin, in which the oxygen is so firmly combined that it is not 
available for the internal respiration of the tissues. Such blood is 
of a reddish-brown or in extreme cases of a coffee color. By reducing 
agents, methaemoglobin is changed to normal haemoglobin, and in this 
way the reducing substances present in normal blood may transform 
small amounts of methaemoglobin to haemoglobin, otherwise cells thus 
affected disintegrate and the coloring matter dissolves in the blood, 
which may cause serious results, such as methaemoglobinuria, blocking 
of the uriniferous tubules, and uraemia. 

Of the substances which thus affect the red cells the most im- 
portant are the chlorates, nitrites, and aniline and some of its deriva- 
tives, especially acetanilide. [Many of the salicylates and other anti- 
pyretics produce analogous changes in the blood to a less degree, but 
still to an extent which may under certain conditions prove of prac- 
tical significance (see p. 478). The sulphones, sulphonal, trional, and 
tetronal form from haemoglobin a pigment, haematoporphyrin, which is 
excreted in the urine. Pyrogallol, much used in photography, should 
also be mentioned in this connection. — Tr.1 

HEMOLYSIS 

Haemolysis, — i.e., a dissolving of the red cells of the plasma — 
occurs if the osmotic tension of the blood sinks appreciably below that 
of these cells. This occurs, for example, if the blood be markedly 
< lil ut c(l by the infusion of pure water. If under special conditions 
the osmotic tension of the corpuscles has been markedly increased 
over that of the plasma, this, too, results in haemolysis. Such may be 
the case if the blood has been strongly concentrated in some portion 
of the body by the injection into the tissues of substances which 
strongly attract water, — e.g., concentrated salt solutions or glycerin. 
(This occurs especially if stasis exists.) If then the distended 
hypertonic red cells pass with the blood into other portions of the 
body where the plasma is of normal tension, they undergo haemolysis 
( Filch ne). 

A hemolytic action is also produced by all substances which 
chemically or physicochemically attack any integral components of the 



452 PHARMACOLOGY OF THE BLOOD 

corpuscular stroma and thus destroy the balance of the normal pro- 
toplasmic combinations. Saponin, on account of its strong affinity to 
cholesterin, exerts this action (Ransom), as do ether, chloroform, and 
all the narcotics of this group, by virtue of their affinity to the 
lecithin present in the red cells. From a practical stand-point these 
toxic actions are of no moment, for saponin cannot pass unchanged 
through the mucous membrane of the alimentary tract and the nar- 
cotics do not attain a sufficient concentration in the blood. [Repeated 
administrations of chloroform, and probably also of ether, do cause 
a distinct anaemia, probably due to this cause, and in the rabbit such 
haemolysis due to ether is frequently observed. — Tr.] The haemolysiu 
contained in Morchella esculenta (Bohm), an edible mushroom, which 
is readily absorbed from the stomach into the blood, is practically 
important. It is removed from the fresh mushrooms by boiling with 
water and appears to be destroyed by drying. It is not known which 
component of the corpuscles it combines with. The same is true of 
AsH 3 , which haemolyzes the blood-cells when inhaled in even very 
small quantities. 

Finally, the hemolytic toxins, such as those in snake venoms, — e.g., 
in cobra venom [and hemolysins formed by bacterial action. — Tr.], — 
should be mentioned, as also haemolysis by heterogeneous sera. 

The effects of haemolysis are very varied. In case of very extensive 
and rapid dissolution of the blood, the setting free of fibrin-ferment 
may cause clotting in the vessels, with fatal results. With less marked 
haemolysis the abnormal amount of dissolved haemoglobin causes an 
abnormally large production of bile-pigments and jaundice, while that 
portion of the haemoglobin which is not retained by the liver and 
spleen is excreted by the kidneys, where it may block the uriniferous 
tubules and cause anuria. 

In haemolysis not only the coloring matter of the blood-cells 
but also their lipoids (lecithin, etc.) and salts enter the plasma. If, 
as is the case in many species, the erythrocytes contain large amounts 
of potassium salts, these may fatally poison the heart. The liberated 
lipoids, if derived from the cells of the same species, are relatively 
harmless, but the heterogeneous ones are extraordinarily poisonous. 
Rabbit's blood injected intravenously into a dog is haemolyzed by the 
dog's plasma, and the liberated lipoids quickly paralyze the respiration 
and the central nervous system (Gottlieb u. Lefmann). It is these 
poisonous components of the dissolved red cells which are responsible 
for the dangerous effects of the transfusion of heterogeneous blood, 
which, when haemolyzed, at once becomes very poisonous. 

BIBLIOGRAPHY 

Bohm u. Kiilz: Arch. f. exp. Path. u. Pharm., 1882, vol. 10, p. 445. 

Filehne: Virehow's Arch., 1889, vol. 117, p. 413. 

Gottlieb u. Lefmann: Med. Klinik, 1907. 

Lefmann: Hofmeister's Beitr. z. chem. Physiol., 1908, vol. 11, p. 255. 

Ransom: Deut. med. Woch., 1901, No. 13. 



CHAPTER XV 

PHARMACOLOGY OF HEAT REGULATION 
ANTIPYRETICS 

All the drugs which exert an influence on the temperature act 
much more strongly on febrile than on normal temperature. How- 
ever, fundamental differences in their action on the normal and on the 
diseased organism exist only in those antipyretics which, like quinine 
in malaria, exert a direct influence on the cause of the fever (see 
Etiotropic Agents, p. 527), while the great majority of the drugs 
of this group exert their influence only on the symptom of increased 
temperature. That even these purely symptomatically active antipy- 
retics lower the temperature of febrile individuals so much more 
markedly than they do that of the healthy is due to the different 
behavior of the heat-regulating mechanism in health and in fever. 

THE HEAT-REGULATING MECHANISM 
The heat-regulating mechanism includes all those processes taken 
as a whole by which the body temperature is maintained constant in 
spite of the changing temperature of its environment. In the cold- 
blooded animals, in which there is no heat regulation, the production 
of heat and the body temperature rise and fall with the external 
temperature, but in the warm-blooded animals heat and cold are 
effective stimuli for a number of physiological processes, whose pro- 
tecting influence enables the organism to maintain its own proper 
temperature in spite of a lowering or raising of the external tem- 
perature. These processes are in part local ones, which occur in the 
cooled or warmed surface of the body, and in part are the results of 
complicated remote actions induced reflexly. 

By the local action of cold, the cutaneous vessels are constricted 
in those regions of the skin which are affected, and the skin becomes 
ana-mic, pale, and cold (F. Frank, Mosso), and, as the skin with its 
cushion of subcutaneous fat is a poor conductor of heat, it acts as a 
protecting cover to the internal organs. On the other hand, heat causes 
local relaxation of the cutaneous vessels and consequently redness 
and a freer flow of blood to the skin. Here these effects are at least 
in part due to a direct action of cold and heat on the vessel walls, 
for even the vessels of a surviving organ which has been isolated from 
the central nervous system dilate under the influence of heat and 
contract under that of cold (Lewaschew, Bernstein, Langendor/f). 
Cold, however, acts not only on the vessels of that portion of the 

453 



454 PHARMACOLOGY OF HEAT REGULATION 

skin which is directly exposed to it, but also on its temperature nerves, 
and, as a result, there is a subjective feeling of cold, for only when 
the skin is poorly supplied with blood and is itself cool do we feel 
cold. Cold also excites reflexes which limit the loss of heat by the 
body and increase its production. 

This limitation of the heat output is brought about by a reflexly 
induced constriction of all the cutaneous vessels, not only in the 
parts directly exposed to the cold but also over the whole surface 
of the body, which becomes pale and anaemic, and consequently a 
general feeling of cold may be produced by the cooling of only one 
part of the body. Such reflexes may be especially well demonstrated 
by plunging one hand into very cold water, in which case the tem- 
perature of the skin of the other hand is found to be diminished 
(Brown-Sequard et Tholozan) . Slight cooling of one arm also causes 
a distinct diminution in the volume of the other, as may be shown 
plethysmographically (Amitin, Lommel). Similarly cold applied 
locally, by diminishing the blood content of the superficial portion of 
the body, especially in the skin and muscles, may cause a very pro- 
nounced alteration in the distribution of the blood, so that the ab- 
dominal organs receive a greatly increased blood supply (0. Miiller). 

This constriction of the cutaneous vessels resulting from the stimu- 
lus of cold protects the organism in a double fashion. First, a smaller 
portion of the total quantity of the blood is exposed to cooling in 
the skin, and consequently the blood returns to the heart at a less 
diminished temperature ; and, secondly, more blood is diverted to the 
internal organs, in which its temperature is raised. As a result of 
this alteration in the distribution of the blood, the loss of heat caused 
by a lowered external temperature is limited, and. the blood tempera- 
ture remains constant so long as this physical heat regulation is suffi- 
cient to accomplish this end. When, however, it alone is no longer 
sufficient, as, for example, when one remains for a considerable time 
in a cold bath, a second regulatory mechanism is called reflexly into 
play, — the chemical heat regulation {Buhner). 

In the latter case the organism protects itself by increased com- 
bustion, as shown by the fact that, when this chemical regulatory 
mechanism is called into play, the carbon dioxide output rises with the 
greatest regularity as the external temperature is gradually decreased 
(Wolpert). This reflexly augmented production of heat occurs 
chiefly in the muscles, and at the start without the occurrence of any 
visible movements, the increase in the production of heat being 
unaccompanied by any performance of mechanical muscular work. 
Besides the muscles, the great glands of the body also play a role 
in the production of heat, so that the reflexes resulting from external 
cold affect the functions of practically all the organs of the body. 

Pharmacologically it is of some significance that the subjective 
feeling of cold and the protective processes which are excited by 



PHYSIOLOGY 455 

stimulation of temperature nerves are dependent on the character 
and extent of the blood flow through the skin, for, if the cooling off 
of the skin is prevented by paralyzing the cutaneous vessels, — e.g., 
by alcohol, — so that these, in spite of the low temperature, continue to 
receive large amounts of blood, the internal temperature of the body 
falls, but the individual does not feel cold because the temperature of 
the skin has not been lowered. Under these conditions, however, the 
stimulus, which causes the normal voluntary and involuntary protec- 
tive reactions, which originate in the skin, is lacking, and, as a con- 
sequence, the body continues to lose more and more heat. This 
is the explanation of the danger of freezing to death which is caused 
by all narcotic poisons which paralyze the vessels' of the skin, a danger 
which is especially great in alcoholic intoxication. 

Like the regulation of the body temperature against cooling, the 
protection against overheating is also controlled by the nervous sys- 
tem, the cutaneous vessels being dilated, the secretion of sweat excited, 
and the respiration accelerated, so that more heat is given off through 
the skin and the lungs, all these effects being brought about by the 
activity of various nervous centres. The dilatation of the cutaneous 
vessels causes a larger quantity of blood to be exposed to the external 
cold, and the evaporation of the sweat from the surface of the skin 
absorbs a large amount of heat which is thus removed from the body. 
On the other hand, animals which are not able to sweat and which 
possess a thick hairy coat get rid of their superfluous heat chiefly 
by rapid breathing and the evaporation of water which results there- 
from. 

Thp dog, for example, is able to augment the heat loss from the skin only- 
very slightly, and consequently he accomplishes his heat regulation by means of 
very rapid breathing, blowing the air over the widely protruded tongue, whose 
broad surface is kept constantly moistened with saliva and mucus and offers 
an exceptional opportunity for the evaporation of water. If dogs be forced 
to work and this very important regulatory mechanism be interfered with by 
previous tracheotomy, death ensues as a result of overheating (Zuntz). 

In man, besides dilatation of the cutaneous vessels, the secretion 
of sweat is the most efficient means of removing large quantities of 
heat from the body, for the evaporation of 1 c.c. of water requires 
as much as 0.54 calorie, and consequently the excess of heat may be 
lost simply by the aid of the physical heat regulation, even during 
the performance of large amounts of mechanical work, as in marching 
{Zuntz), and, therefore, there is no need of a chemically regulated 
limitation of the production of heat to protect the organism from 
overheating. 

Such regulation against overheating can also be directly called into 
play by a very slighl increase in the temperature of the blood, for, 
without altering flic temperature of the blood in the rest of the body, 
all the signs of the physical regulation against overheating may be 



456 PHARMACOLOGY OF HEAT REGULATION 

caused to appear by simply warming the blood in the carotid on its 
way to the brain, this, alone being sufficient to cause dilatation of 
the cutaneous vessels, increased secretion of sweat, and heat dyspncea 
(Eahn). 

It is thus apparent that the heat-regulating centres can be stimu- 
lated to their reaction against a low external temperature not only 
reiiexly but also by a diminution, even though a minimal one, of the 
temperature of the blood (Stem, Strasser), while in their reaction 
against overheating they are influenced both by the temperature of 
the blood and also reflexly from the skin, for such signs of com- 
pensatory regulation as sweating can appear under the influence of 
heat stimuli even before any augmentation of the temperature of the 
body has occurred (Stem, Strasser, Filehne). While this is true, 
still under all conditions it is the central nervous system which 
keeps the body temperature constant. 

From what has already been said, it is evident that the physi- 
ological regulation of heat is accomplished by a very complicated 
mechanism, in which the vasomotor and secretory centres are in- 
fluenced by a higher centre or centres. The organs in which the 
loss of heat occurs are connected nervously through such heat-regulat- 
ing centres with the organs — the muscles and the glands — in which 
the heat is produced. Up to the present, however, our knowledge of 
the details of this relationship between these various regulatory pro- 
cesses is very incomplete. Certain it is only that the temperature 
equilibrium is maintained by this mechanism in such fashion that the 
production and output of heat always keep pace with each other so 
long as the heat-regulatory mechanism in the central nervous system 
continues to function normally. Under all the changing conditions 
of external temperature, as also in spite of all variations in the com- 
bustive processes in the organism, the body temperature remains 
constant, because, with every change in the metabolism, — as, for ex- 
ample, when food is ingested or when muscular work is performed, — 
the output of heat simultaneously changes in a corresponding direc- 
tion, and because, if this physical regulation does not suffice, the pro- 
duction of heat is also regulated so as to correspond to the changing 
demands occasioned by the loss of heat. In this fashion the equilib- 
rium of the heat economy of the body can be maintained, even 
in spite of very great variations in the amount of heat produced or 
lost. The maintenance of the normal body temperature depends simply 
on any alteration of one factor being compensated by a regulatory 
alteration of the other, so that the momentary heat loss may always 
equal the momentary heat production, the amount of heat in the body 
being thus kept constant. 

These relationships may be expressed by a diagram (see Fig. 55), 
in which the changing values of heat production and output are shown 



PHYSIOLOGY 



457 



as ordinates. Under normal conditions they coincide with each, other, 
and there is no interval between them so long as the body temperature 
remains normal. 

The curve below represents the body temperature under different 
conditions. It remains normal if under normal conditions the pro- 
duction and output of heat are equal, also when both are equally in- 
creased, as, for example, during muscular work. In long-continued 
hunger the body temperature falls as a result of the diminution of the 
production of heat. In fever it rises, because of the lagging behind 
of the heat output and because of the increase in the heat production 
which then follows. In the crisis it falls, because the heat production 
lags behind the heat output. 




Pitfliiiiinii 



Work Rest, fasting Normal 


Chill 


Fastigium Crisis \ Normal 


Heat production 




Sweating 

| 


Heat loss 




Subnormal 



Fig. 55. 

Such a coordinated cooperation between heat production and heat 
loss could be obtained only by a centrally connected control of both 
processes, for the controlling heat centres must necessarily be able 
both to influence the organs through which heat is lost and to control 
the metabolism in the tissues. 

The reaction of these heat centres to cooling may be interpreted 
as consisting in an augmented state of excitation of the regulating 
centres. Even under normal conditions stimuli are carried through 
the sensory centres of the skin to the centres for the constriction of 
the cutaneous vessels, and, if the temperature of the skin falls, tins 
reflex stimulation becomes stronger, and consequently the heat out- 
put is diminished. The chemical heat regulation, — that is, the aug- 
mentation of the processes by which heat is produced, — which is 
excited by cooling of the body, also depends upon an augmentation of 
the nervous impulses which accelerate the chemical processes in the 
muscles, which can even be so augmented as to cause visible muscular 
movements, such ;is Bhivering when one is chilled. That this conser- 
vation and production of heat is due to an augmented excita- 
tion of the centres is indicated, above all, by the fact that the same 
effects, diminution of the output and augmentation of the production 
of heat, may also be produced by direct mechanical or electrical stinro. 



458 PHARMACOLOGY OF HEAT REGULATION 

lation of certain regions of the brain (Aronsohn u. Sachs, Bichet, 
Ott) . In the rabbit, dog, and horse such a point lies in the head of the 
corpus striatum. 

The reaction of the organism against overheating can, on the other 
hand, be assumed to be due to a depression of the excitability in the 
same centres, these centres, under the influence of overheated blood, 
moderating the impulses which they send to the vasomotor centres. 
In accordance with this is the observation of Kahn that overheat- 
ing of the carotid blood acts as a sedative on other centres also, 
the animals being, as it were, narcotized. These assumptions are in 
no way inconsistent with the fact that, associated with this sedative 
action on these regulatory controlling centres, there is an augmented 
activity of the subsidiary centres, which causes secretion of sweat, 
heat dyspnoea, etc., for often enough in physiology one meets with 
examples of such opposing actions on controlling and subsidiary 
centres. 

It will be shown later that the actions of pyrogenous poisons and of 
antipyretics are quite consistent with this assumption that conserva- 
tion of heat is due to a stimulation of the heat-regulating centres, and 
that increased output of heat is due to sedative action on them. 

Although we speak of heat-regulating centres, it is by no means implied 
that these have been anatomically located, for anatomically we know of no 
heat centre. The structures affected by the heat puncture may be centres or 
— and quite as probably — simply nervous tracts which are connected with 
various scattered centres. However, we are forced to assume in a physiological 
sense a heat-regulating centre, meaning by this term a controlling central 
mechanism, which secures a coordinated cooperation of vasomotor and sweat 
centres, and which also furnishes the necessary nervous impulses to control the 
metabolism, so that the equilibrium of the temperature may be maintained. 
These centres certainly do not lie lower than the midbrain, for, after destruc- 
tion of this or after high division of the cord, warm-blooded animals behave 
like cold-blooded animals, their body temperature becoming dependent on the 
temperature of the environment. 

BIBLIOGRAPHY 

Amitin, S.: Ztschr. f. Biol., 1897, vol. 35, p. 13. 

Aronsohn u. Sachs: Pfliiger's Arch., 1885, vol. 37, p. 232. 

Bernstein: Lehrb. d. Physiol.. Stuttgart, 1894, p. 110. 

Brown-Sequard et Tholozan, cited by Morat et Doyon: Traite de Physiol., 1899, 

vol. 3, p. 490. 
Filehne, O.: Arch. f. Physiol., 1910, p. 501. 
Franck, Francois: Traveaux du Laboratoire de Marey, 1876. 
Kahn, R. H. : Engelmann's Arch. f. Phvsiol., 1904, Suppl., p. 90. 
Langendorlf : Pfliiger's Arch., 1S97, vol. 66, p. 387. 
Lewaschew: Pfliiger'9 Arch., 1881, vol. 20, p. 60. 
Lommel : Deut. Arch. f. klin. Med., 1904. 
Mosso: Archives italiennes de Biologie, 1889. 
Miiller, O. : Habilitationsschrift, Tubingen, 1905. 
Ott: Journ. of Nervous and Mental Diseases, 1884. 
Richet: Compt. rend., 1884 and 1885. 
Rubner: Biologische Gesetze, Marburg, 1887. 
Stern, R. : Ztschr. f . klin. Med., vol. 20, p. 63. 
Strasser: Med. Klinik, 1910, No. 28. 
Wolpert: Arch. f. Hygiene, 1898, vol. 33, p. 206. 
Zuntz: Vortr. Balneolog. Gesellsch., March 6, 1903. 



MECHANISM OF FEVER 459 

FEVER 

In infectious diseases pyrogenous substances, by their action on 
the heat-regulating centres, cause a rise in the body temperature 
(Krehl), for bacterial toxins cause a toxicogenic decomposition of 
proteicls, and the peculiar products of this pathological decomposition 
of protoplasm or the bacterial toxins themselves disturb the normal 
processes of heat regulation. 

Various investigations of the production and conservation of heat 
in febrile men and animals (Krehl u. Matthes) have shown that, as 
a rule, while the heat production is distinctly augmented, this aug- 
mentation is not very great, amounting to only about 20-30 per cent, 
increase above the normal value (Krehl). Inasmuch as in the organ- 
ism, so long as the heat regulation is functioning normally, the pro- 
duction of heat may be increased as much as 60 per cent, by the free 
ingestion of food, and by muscular work even more, without the tem- 
perature rising, it is evident that a 30 per cent, increase in heat 
production cannot by itself be the cause of the augmentation of the 
temperature, and consequently in fever there must also be some other 
disturbance of the temperature regulation. This is in fact the 
case, for, while normally an increase in heat production is readily 
compensated for by increased heat output, this latter is either ab- 
solutely diminished in fever or is less increased than is the heat pro- 
duction. 

Calorimetric determination of the total heat output of febrile animals 
[Krehl u. Matthes) shows that this is diminished during the period in which 
the fever is rising, and in man the coldness and pallor of the skin during the 
chill, by themselves, show that the cutaneous vessels are contracted. This has 
been definitely proven by Maragliano's plethysmography studies and by Geigel's 
and Kraus's thermo-electric investigations. Furthermore, G. Rosenthal's partial 
calometric observations have demonstrated the diminution of the heat loss by 
conduction and radiation. 

It is thus evident that in fever the temperature rises as a result 
of limitation of the heat output while at the same time the heat 
production is, as a rule, augmented. In fever the organism behaves 
as if it were necessary to conserve Its heat, combusting more material 
than ordinarily and parting with as little of its heat as is possible. 

One might be tempted to conclude that in fever the heat centres 
had entirely lost control of the peripheral mechanism by which heat 
is last and produced, and that consequently they are no longer able 
to maintain a balance between these two functions. This, however, 
is not at all the case, for, as shown by Licbcrmcistcr and Stem in man, 
and by numerous others (Colasanti, Finldcr, Lilienfcld, etc.) in 
febrile animals, the febrile organism reacts to cooling influences by 
augmentation of heat production and to artificial overheating by 
increasing its boat output. However, the heat regulation is no longer 
so efficient or complete as in normal conditions, and consequently the 



460 PHARMACOLOGY OF HEAT REGULATION 

febrile temperature is* more readily altered by external influences 
than is the normal temperature. 

From the above it is evident that in fever the body has by no 
means lost its power of heat regulation, but, as production and loss of 
heat are no longer so controlled that the normal temperature is main- 
tained and as, on the contrary, the febrile organism regulates these 
processes in such a fashion that it maintains its abnormal tempera- 
ture, we are compelled to conclude that in fever the heat-regulating 
centres function in an abnormal fashion. As long ago as 1875, such 
observations led Liebermeister to formulate the hypothesis that in 
fever the heat regulation is " set " for a higher temperature. As 
a matter of fact, at the height of any fever a regulatory augmentation 
of the heat output occurs, for otherwise the temperature of the body 
would rise constantly higher and higher because of the constantly 
increasing augmentation of heat production. However, so long as the 
pathological condition of the heat centres persists, the heat loss is 
augmented only enough to maintain the temperature at a febrile 
height, but not enough to bring it back to normal. 

To-day it is possible to form a more precise conception of the 
manner in which in fever the heat mechanism is " set " for an abnor- 
mal temperature, and of the manner in which this is corrected by an- 
tipyretics (Filehne). An analogy between infectious fever jjid punc- 
ture hyperthermia has been of much assistance here, for it has been 
found that heat regulation in both of these types of fever is essentially 
similar. In the fever resulting from the mechanical irritation of the 
corpus striatum there is an augmentation of the heat production 
(Schultze), while during the period of rising temperature the heat 
output is absolutely diminished or at least relatively insufficient 
{Gottlieb, Richter, Schultze), just as in infectious fever. In it, too, 
the power of regulating the temperature is retained and comes into 
action when the external temperature changes (Schultze). At the 
height of the fever thus produced, the heat output is augmented, just 
as in infectious fever, but only enough to enable the organism to 
maintain its febrile temperature. It is thus seen that there is a wide- 
reaching analogy between puncture hyperthermia and infectious fever. 

Although the pathological condition of the heat-regulating mechan- 
ism is essentially the same in both cases, it is due to different causes, 
for the disturbance produced by the heat puncture is a direct one, 
and consequently less complicated, while the alteration of this func- 
tion in fever is due to the action of toxins and is accompanied by all 
the other effects of the infection. 

This accounts for certain differences in the two types of the fever. For 
example, in puncture hyperthermia primarily non-nitrogenous material is com- 
busted, apparently chiefly the glycogen of the liver and muscles (Hirsch u. 
Roily), while in infectious fever it is principally nitrogenous material rendered 
available by the pathological decomposition of proteid which furnishes the 
material for the increased combustion. When the reserve substances have 



MECHANISM OF FEVER 461 

been completely consumed, heat puncture causes no fever (Hirsch), a fact 
-which has been interpreted by some as indicating an essential difference between 
it and true fever. However, the occurrence and extent of the increased com- 
bustion both depend upon the presence of readily available material, which in 
true fever is always available in the form of nitrogenous material resulting 
from the decomposition of protoplasm, although ordinarily such material is 
tenaciously protected in fasting and emaciated individuals. 

However, this difference between puncture hyperthermia and infectious 
fever is not a fundamental one, for in fasting animals it has been found that 
no rise of temperature results from the injection of albumoses and other 
pyrogenous substances which ordinarily cause a septic fever (Krehl u. Matthes) . 

Consequently, everything speaks for the assumption that the 
fever of infection and that following heat puncture are due to a 
basically similar action upon the heat-regulating centres. This 
parallelism between the two types is of importance for our under- 
standing of the pathology of fever as well as for our understanding 
of the action of the antipyretics, for the augmentation of the tempera- 
ture following the heat puncture is, without any doubt, to be at- 
tributed to the trauma's causing a stimulation of the heat-regulating 
centres. The main evidence that this is so is found in the fact that 
the temperature may be augmented by electric stimulation by means 
of electrodes fixed at the proper place in the corpus striatum. We 
may then conclude that the alteration of the heat regulation resulting 
from heat puncture is due to stimulation or irritation of these centres, 
and are justified in assuming the same for fever. When we say then 
that the heat-regulating mechanism is " set " for a higher tempera- 
ture, we mean that the heat-regulating centres are in a condition of 
pathologically augmented excitability. 

While in puncture hyperthermia this excitation is produced by 
mechanical or electrical irritation, in infectious fever we are dealing 
with an irritation produced by toxic substances, parallels for which 
may be found in the various other symptoms of irritation observed 
in fever. In both cases the excitability of the heat-regulating centres 
is so altered that they react so as to conserve heat to stimuli which 
are weaker than those ordinarily adequate, — i.e., this reaction occurs 
without any actual cooling of the body. However, in a normal 
reaction to cooling, the excitation of the centres lasts only as long as 
is necessary to maintain the body temperature, but when their excita- 
bility is pathologically increased the augmentation of metabolism 
and the limitation of heat output persist until that degree of tempera- 
ture is attained at which the sedative action of the increased tem- 
perature of the blood counterbalances this. When, then, in the course 
of the sickness the augmented excitability passes off again, the centres 
react once more in a normal fashion to the overheated blood, so that 
the heat output is again augmented until the normal temperature is 
regained. 

Thorn is no contradiction between this conception of fever, as due in a, per- 
sistent abnormal stimulation of the heat-regulating mechanism, and the well- 
known fact that, generally speaking, the body temperature in fever is more 



462 PHARMACOLOGY OF HEAT REGULATION 

unstable than in health, for a similar behavior of irritated organs is often 
enough observed (Loewi). The slighter resistance manifested by the febrile 
organism to frigorifie influences may be conceived of as the expression of the 
fact that the irritated centres are more readily fatigued. 

From the foregoing, the action of pyrogenous substances must be 
attributed to a stimulation or an augmentation of the excitability of 
the heat-regulating mechanism. Fever results from the invasion of 
the pathogenic organisms, and persists as long as the body, with the 
assistance of its defensive weapons (antitoxins, b^acteriolysins, etc.), 
is able to continue the battle; but when it succumbs, collapse de- 
velops and the temperature falls. It consequently appears probable 
that certain substances, which are formed as a result of the death 
of the pathogenic organisms, act as pyrogenic poisons, which stimu- 
late the heat-regulating centres and in larger amounts paralyze them. 
Heterogeneous proteid also, when it disintegrates in the body, causes 
a rise of temperature, which, under the peculiar conditions of hyper- 
susceptibility to heterogeneous proteid, expresses itself as an anaphy- 
lactic fever. Moreover, the decomposition products of homologous 
cells — for example, the albumoses — alsp act as pyrogenetic agents 
(Krehl u. Matthcs). Apparently a large number of substances, par- 
ticularly when administered intravenously and in the presence of 
hypersusceptibility, cause a septic fever by causing decomposition 
of cells or of proteid (Krehl). While the mechanism by which this 
is accomplished has not been cleared up, it is not improbable that 
a stimulation or augmentation of the excitability of the sympathetic 
nervous system, to which consequently the heat-regulating centres also 
probably belong, plays a causative role in the production of such fever. 

In favor of this view is the fact that tetrahydronaphthylamine 
(see p. 159) has a marked power of raising the temperature (B. 
Stern), and that, moreover, many drugs, like caffeine, cocaine, and 
atropine, which, generally speaking, stimulate many of the nervous 
centres, cause an increase of the temperature, even quite independently 
of the secondary effects of any convulsions which they may cause. 
These are all drugs which cause other symptoms of stimulation of 
the sympathetic or depression of the antagonistic autonomic system, 
such as pulse acceleration, mydriasis, psychic stimulation, etc. 

That, on the other hand, other drugs which also stimulate various 
centres, such as the eonvulsant poisons like santonin, picrotoxin, 
aniline, phenol, etc., do not raise the temperature, but in fact under 
certain conditions markedly depress it (see p. 473), does not speak 
against such a conception, but rather confirms our interpretation, for 
these drugs do not stimulate the sympathetic nerves, but, on the 
contrary, stimulate the antagonistic autonomic centres, causing slow- 
ing of the pulse, miosis, psychic depression, etc. Finally, moreover, 
the typical sympathetic poison, epinephrin, can under certain con- 
ditions cause a marked augmentation of the temperature (Eppinger, 
Falta u. Budinger), and it appears probable that this epinephrin 



ANTIPYRETICS IN FEVER 463 

fever is due to a central or peripheral stimulation of the sympathetic 
system. In the fasting animal and in narcosis, epinephrin causes no 
rise in temperature, and calcium salts, which depress the excitability 
of all organs which are susceptible to epinephrin, also prevent or 
lower fever thus caused (Freund). 

According to this last-mentioned author, sodium-chloride fever 
is of a similar type. This was first observed in infants after the ad- 
ministration of large quantities of common salt (Finkelstein, Schloss), 
but may also be induced in adults in about 50 per cent, of the cases 
(Bingel), and even more readily in animals. It would appear that 
this sodium-chloride fever is also due to stimulation of the sympa- 
thetic nervous system.* 

BIBLIOGRAPHY 

Bingel: Arch. f. exp. Path. u. Pharm., 1910, vol. G4. 

Colasanti: Pfliiger's Arch., 1877, vol. 14, p. 125. 

Eppinger, Falta u. Rudinger: Ztschr. f. klin. Med., vol. 66. 

Filehne: Berl. klin. Woch., 1882, No. 45; 1883, No. 6. 

Filehne: Kongress f. Innere Medizin, 1885. 

Finkelstein: Deut. med. Woch., 1909, p. 491. 

Finkler: Pfliiger's Arch., 18S2, vol. 29, p. 89. 

Freund: Miinchn med. Woch., 1911, No. 6. 

Geigel : Verhandl. d. Phys.-med. Ges., Wiirzburg, 1889, vol. 22, No. 1. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1891, vol. 28, p. 167. 

Hirsch u. Roily: Deut. Arch. f. klin. Med., 1903, vol. 75, p. 307. 

Kraus: Wien. klin. Woch., 1894, p. 229. 

Krehl: Patholog. Physiol., 4th edition, Leipzig, 1906. 

Krehl: Arch. f. exp. Path. u. Pharm., 1895, vol. 35, p. 222. 

Krehl u. Matthes: Arch. f. exp. Path. u. Pharm., 1895, vol. 36, p. 451; vol. 37, 

p. 232; 1897, vol. 38, p. 284. 
Liebermeister : Path. d. Fiebers, Leipzig, 1875, p. 341. 
Lilienfeld: Pfliiger's Arch., 1883, vol. 32, p. 293. 
Loewi : Ergebnisse d. Physiol., 1904, vol. 3, p. 332. 
Maragliano: Ztschr. f. klin. Med., 1888, vol. 14; 1890, vol. 17. 
Richter: Virchow's Arch., 1891, vol. 123, p. 118. 
Rosenthal, C: Arch. f. Anat. u. Phys., 1888, p. 1. 
Schaps: Berl. med. Woch., 1907, p. 597. 
Schloss: Biochem. Ztschr., vols. 17 and 22. 
Sclmltze: Arch. f. exp. Path. u. Pharm., 1899, vol. 43, p. 193. 
Stern, R. : Virchow's Arch., 1889, vol. 115; 1890, vol. 121. 
Stern: Ztschr. f. klin. Med., 1892, vol. 20, p. 63. 

ACTION OF ANTIPYRETICS IN FEVER 
The conception of fever as caused by over-excitability of the heat- 
regulating centres is useful in explaining the antipyretic effects of 
certain drugs, in considering which it is advantageous to use as a 
starting-point the simpler fever that follows puncture (Gottlieb). 

If the fever following heat puncture in the rabbit be allowed Id 
run its course without interference, the curve exhibits the char- 
acteristics of continuous fever. 

* [As a result of recenl investigations of the effects of ihp intravenous injec- 
tion of normal saline solutions made up with freshly distilled water as con- 
trasted with those made up with dislilled water which had stood some time, 
Considerable doubt has been thrown on the earlier experiments which appeared 
to demonstrate the possibility of a sodium chloride fever. — Tb.] 



464 



PHARMACOLOGY OF HEAT REGULATION 



After the preliminary fall of the temperature due to the shock of 
the operation, the fever within a few hours rises markedly, and 
maintains itself without marked variation for 12-24 hours at about 
41-42° C. and then very gradually returns to normal. 

June 7 June 8 June 9 

h 3 * S 6 7 8 S to 11 12 I 2 3*56 10 11 12 / 2 8 



vz 




























t 


, 


















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/ 
























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/ 


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Figs. 56. — Normal course of puncture hyperthermia. 

In other particulars such rabbits manifest no other disturbances 
of function, and continue to eat and appear quite normal. A dose of 
antipyrine causes a sharp depression in this very regular course of 
the temperature curve. 

Without producing any other noticeable effects, 0.5 gm. of antipyrine ad- 
ministered to such a rabbit brings the temperature back to normal, but after 
about two hours the temperature commences to rise again, and after about 6-8 
hours, when the effects of the drug have passed off, regains its original height. 

The more the effects of the puncture in causing stimulation of the 
heat centres have passed off before the antipyretic is administered, 
the greater is the effect of the drug in bringing about a changed 
" setting " of the centre, — i.e., in lessening its excitability. Con- 
sequently, at the summit of the temperature curve or in the descend- 



h 7 


8 


9 


to 


11 


12 


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Fig. 57. — Effect of antipyrine on puncture hyperthermia. 

ing portion, antipyrine acts more strongly than during the period in 
which the temperature is rising rapidly. The other drugs belonging 
to the same pharmacological group act here just like antipyrine. 

It is of decisive importance for the interpretation of these 
phenomena that, on the one hand, the puncture hyperpyrexia is 
conceived of as due to stimulation of the heat centres and that, on the 
other hand, all typical antipyretics are narcotic in their nature. 
Consequently it may be concluded that the antipyretics owe their 



ANTIPYRETICS 



465 



action to their power of acting as sedatives to the pathologically 
stimulated heat centres. If any further proof of the correctness of 
this conception "were necessary, this is furnished by the observation 
that other drugs which without any doubt act as central depressants — 
for example, small doses of morphine — lower the temperature of 
puncture hyperthermia, even in the rabbit, which is, generally speak- 
ing, very insusceptible to this drug. 



July 12 
h 70 // ?2 / 2 3 $ 3 6 7 



July 13 
ff 12 1 2 3 *t 3 6 















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t 






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Fig. 58. — Effects of morphine and of antipyrine on puncture hyperthermia. 



The antipyretics consequently are narcotics of the heat-regulating 
centres of the brain. Their basic narcotic character, however, does 
not show itself solely in their sedative action on the heat-regulating 
mechanism, for their mild depressing action is just as clearly mani- 
fested in the sensory portion of the cerebral cortex. Consequently 
the more powerful antipyretics cause a more or less pronounced con- 
dition of sleepiness and of diminished sensibility in laboratory ex- 
periments. Above all, however, clinical experience has taught us 
that all the antipyretics are at the same time analgesics and seda- 
tives, — i.e., mild narcotics for the sensory cerebral tracts. 

From what has already been stated, it is clear that the com- 
bination of antipyretic and sedative action in all the drugs of this 
group is not merely a coincidence, for both of these properties are 
the expression of a mild narcotic action on the cerebrum, the elective 
seats for this action being assumed to lie, on the one hand, in the 
cerebral cortical centres for the perception of pain (just as is the case 
with morphine) and, on the other hand, in the heat-regulating cen- 
tres which are over-stimulated in fever. For these reasons Schmicde- 
berg has very appropriately given to the drugs of the antipyrine group 
the name of fever narcotics. This name, moreover, correctly character- 
izes this group of drags, inasmuch as modern medicine employs them 
in fever but seldom as a means of combating the hyperpyrexia as 
such, but rather in the hope that the patient will be benefited by their 
sedative action on all those symptoms of fever which are dne to over- 
excitability of the centres. 

It is quite in accord with the conception of the antipyretics as 
sedatives of the heat eentres that those dos-s which are effective in 
fever do not influence the temperature in health, although larger doses 
30 



466 PHARMACOLOGY OF HEAT REGULATION 

do produce a lowering of the temperature even in health. The ex- 
planation of the stronger effect on the excitable heat centres of fever 
is found in the general experience that nervous centres, when in a 
condition of persistent over-excitability, are, as a rule, more readily 
fatigued, and consecpiently more susceptible to the action of narcotics. 
The same thing is observed to a very striking extent in the physio- 
logical effects of strychnine, in which over-excitability and ready 
exhaustibility of the reflex centres go hand in hand. 

The therapeutic action of the antipyretics as described thus far 
should, however, be clearly differentiated from a true paralysis of the 
heat-regulating mechanism, for, after effective doses of antipyrine, 
animals still react very decidedly to changes in the external tempera- 
ture, although not so promptly as untreated controls. The power of 
regulating the body temperature is lost only after very much larger 
doses, this being simply one of the results of the general collapse 
which is caused by larger doses. 

Collapse. — Numerous poisons and drugs cause collapse with a marked 
fall of blood-pressure, both effects being the result of a commencing paralysis 
of the vital centres. Particularly with the narcotic drugs and poisons the 
therapeutically effective doses lie relatively near to those which cause col- 
lapse. Like the narcotics, substances of the carbolic acid group, the salicy- 
lates, and members of the antipyrine group, all of which are closely related 
pharmacologically, produce such conditions of paralysis relatively easily. In 
such collapse the temperature of the body falls, but this lowering of the 
temperature by depressing the various nervous centres differs from the elective 
antipyretic action in its entirely different symptomatology and in the different 
manner in which it is produced. In collapse, as the temperature falls, the 
pulse becomes small and weak, the extremities grow cold, and all those 
symptoms develop which are spoken of as cardiac weakness. As a result 
of depression of the vasomotor centres, the rapidity of the blood circulation 
is so diminished that only small amounts of heat are lost through the skin, 
and at the same time the heat production is diminished as a result of a 
centrally induced diminution of heat production (Krchl u. Matthes). 

There is no doubt that a number of drugs formerly much used in fever — ■ 
for example, veratrum and aconite — produce a narcotic effect on the over- 
excited heat-regulating centres similar to that produced by our modern anti- 
pyretics. However, they differ from these latter in that their actions are 
not so electively confined to the heat-regulating mechanism, and, as a con- 
sequence, with them antipyretic effects result only from such doses as lie very 
close to the dangerous ones which may cause collapse. As a consequence, these 
drugs have been abandoned, and correctly so (see pp. 109, 426). 

Pyrogenic poisons also very readily cause collapse, causing in 
small doses an augmentation and in larger doses a fall of the tem- 
perature, which is accompanied by a diminution of both the produc- 
tion and the output of heat (Erehl u. Matthes). Fever may, there- 
fore, be considered as a symptom of stimulation produced by small 
amounts of toxins, and collapse as a symptom of the paralysis caused 
by larger amounts of these substances. 

BIBLIOGRAPHY 
Gottlieb: Arch. r. exp. Path. u. Pharm., 1800. vol. 20, p. 419. 
Krehl u. Matthes: Arch. f. exp. Path. u. Pharm., 1897. vol. 38, p. 299. 
Schmiedeberg : Grundriss d. Pharmakol., Leipzig., 1909. 



COLD BATHS 467 

COLD BATHS 

Following the discussion of the more pronounced alterations of 
febrile temperature produced by antipyretic drugs, the entirely anal- 
ogous action of cold baths should be briefly considered. 

The temperature of a healthy individual does not fall at all as 
a result of such moderate abstraction of heat as results from ordinary 
hydrotherapeutic measures. In fact, at the start the internal tem- 
perature rises for a short time (Liebermeister) , because, by the con- 
traction of the cutaneous vessels, the blood is driven out from the 
region in which normally it is cooled, and it is only during the so- 
called primary after-effect that the temperature may fall slightly, 
if after the bath the cutaneous vessels relax so that larger than 
normal amounts of blood may flow through the cooled-off skin.* 
Under normal conditions, the physical regulation by constriction of 
the cutaneous vessels and the chemical regulation by increased com- 
bustion of non-nitrogenous substances are sufficient to keep the tem- 
perature of the body constant within very narrow limits. However, 
the power of heat regulation, even in health, has a limit, and the 
temperature of the body sinks if the temperature of the bath 
is extremely low and its duration very long, this occurring more 
readily in small and poorly nourished than in large and fat indi- 
viduals. 

In the febrile patient, on the other hand, the temperature is much 
more markedly lowered even by very moderate cooling, and often 
remains somewhat depressed for hours. It is thus evident that in 
fever the heat regulation exhibits the same instability in its reaction 
to measures by which heat may be abstracted as to medicinal anti- 
pyretics. Just as with antipyrine, the heat production in a febrile 
individual is augmented to a slighter degree by abstraction of heat 
than is the case in health. Particularly in the period of after-action, 
in which the diminution of the temperature becomes more pronounced, 
the chemical heat regulation of the febrile patient more readily proves 
itself insufficient. This effect is augmented further by the fact that 
in many febrile conditions the vasomotor centres tire particularly 
easily, so that, after being contracted during the bath, in the after- 
period the tone of the cutaneous vessels is markedly diminished and 
for a considerable period (Krehl).* 

BIBLIOGRAPHY 
Krehl: Patholog. Physiol. 

Liebermcister: Pathologic 'I. Kiehcrs. 

* [Such reaction lb favored by continuous friction of the body during the hath. 
That this is so may be readily demonstrated by comparing the after-effects on the 
temperature produced by baths given with such friction, with those following 
similar baths given without it. — Tr.] 



468 PHARMACOLOGY OF HEAT REGULATION 



DIRECT ACTIONS OF THE ANTIPYRETICS ON HEAT PRODUC- 
TION AND HEAT LOSS 

Thus far we have spoken as if only the central heat-reflating 
mechanism were affected by the antipyretics. On closer examination, 
however, the conditions are found to be more complicated. This is 
dependent on the fact that the action of the antipyretics is not limited 
to the heat-regulating centres alone, but that certain of them also 
affect the heat economy of the body by influencing the output or 
formation of heat independently of the central regulating mechanism. 
From this point of view we may differentiate between two groups of 
antipyretics : 

Those of the antipyrine group, which cause cutaneous vasodilata- 
tion and directly increase the heat loss ; and 

Quinine, which lessens the production of heat by a direct action 
on the various metabolic processes in the tissues. The phenomena of 
defervescence, as it actually occurs, are in part due to these direct 
actions on the functions of heat output and heat production. 

ACTION OF THE ANTTPYRTNE GROUP OX THE HEAT OUTPUT 
If antipyrine acted only on the central heat regulation, and 
changed the over-excitability of the centres to a normal condition with- 
out directly and independently interfering with the heat economy of 
the body, it should be expected that under its influence the body would 
get rid of its superfluous heat in the same fashion as in spontaneous 
defervescence. In spontaneous reduction of the temperature the pro- 
duction of heat is reduced to the normal or even below this (Krehl u. 
Matthes), but, above all, the output of heat is so influenced that 
critical defervescence in infectious diseases is followed by "marked 
dilatation of the cutaneous vessels and profuse sweating. The same 
phenomena then should occur if a dose of antipyrine has brought 
about a normal condition of the heat centres, and, as a matter of fact, 
in defervescence produced by antipyrine the behavior of the organism 
corresponds in many cases to this type (Stilhlinger) . 

However, it does not always do so, for antipyrine possesses the power 
of dilating the cutaneous vessels independently of the heat-regulating mechanism 
and to an even greater degree, and even in health this effect may be produced 
by doses which do not lower the temperature, and which consequently are 
incapable of affecting the tone of the more resistant heat-regulating centres of 
the healthy individual. As a result of this cutaneous vasodilatation, antipyrine 
increases the heat loss in health as well as in fever. That the temperature 
does not fall is due to a compensatory augmentation of the heat production, 
which opposes the alteration of the temperature as long as the heat-regulatory 
mechanism is capable of functioning normally (Gottlieb). This compensatory 
augmentation of combustion is the explanation for the often considerably in- 
creased excretion of nitrogen which antipyrine and related substances cause 
in healthy men in whom the heat regulation acts promptly. 

While in the healthy man this prompt regulation of temperature is over- 
come only by much larger doses than are used therapeutically, in fever such 



ANTIPYRINE GROUP 



469 



doses of antipyrine do weaken this regulatory function, and, as a consequence, 
there is no longer so great an increase in the heat production as there is in 
the heat loss, and consequently the body temperature falls. 

This attempt of the organism to combat the augmented heat loss caused 
by antipyrine is also manifested in many cases of fever when the temperature 
falls, causing, just as in the healthy individual, a compensatory augmentation 
of heat production, which is not to be disregarded, for it necessarily results in 
an increased consumption of tissues. This regulation against heat loss is, it 
is true, often but slight in febrile patients (Riethus), and consequently the 
diminution of heat production which results from the defervescence more than 
counterbalances it. The reduction of febrile temperature by antipyrine may 
be schematically represented in the accompanying diagram. 



— 39" 
— 380 
—370 



*■». Body temperature 



-36° 



Commencement of 
antipyrine act 



Cessation of 
antipyrine action 

Normal tem- 
perate 




_...... — ...Heat production 

— — — —Heat loss 

Fig. 59. — Antipyretic effect of antipyrine. Augmentation of heat loss with 
slight compensatory increase in heat production. 



Antipyrine and related substances consequently reduce the tem- 
perature principally by augmenting the heat loss, as is indicated 
by the simple direct observation of the hot and reddened skin and as 
has been demonstrated thermoelectrically by Geigel and plethysmo- 
graphically by MaragUano. This cutaneous vasodilatation is not 
simply one symptom of a generally, diminished vascular tone, but is 
the result of an antagonistic behavior of the vessels of the skin and 
those of the internal organs. As this does not lower the general 
blood-pressure, and may in fact increase it, large quantities of blood 
are caused to flow through the dilated vessels on the surface of the 
body, where the fever-heated blood has an opportunity to give off its 
.superfluous heat, this bringing about an increase in the heat output, 
which has been demonstrated both in animals (Gottlieb u. Bichtcr) 
and, by partial calorimetry, in man (Rosenthal) . 

It must again be emphasized that the above-described augmenta- 
tion of the heat loss is not the true cause of the antipyretic action of 
antipyrine, for the augmentation of heat loss, which, according to 
e;ih>ri metric determinations, seldom exceeds the normal by more than 
20-30 per cent,, is much too slight to overcome a, normally functioning 
heat regulation. Consequently, in a healthy man the temperature is 
not altered, in spite of sueli increased heat output, but, owing to 
the greater ease with which the over-stimulated and at the same time 



470 PHARMACOLOGY OF HEAT REGULATION 

readily fatigued centres of fever may be influenced, even smaller 
doses are sufficient to produce a sedative effect on the heat-regulating 
centres. This sedative action on the central heat regulation is to 
be considered as the real cause of the antipyresis, while the directly 
produced augmentation of the heat loss is to be regarded simply as 
a simultaneous clearing of the paths by which the superfluous heat 
is eliminated. 

BIBLIOGRAPHY 

Geigel: Verh. d. Physik.-med. Ges., Wiirzburg, 1889, vol. 22, No. 1. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1891, vol. 28, p. 167. 

Krehl u. Matthes: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 284. 

Maragliano: Ztschr. f. klin. Med., 1880, vol. 14, p. 309. 

Richter: Virchow's Arch., 1891, vol. 123. 

Riethus: Arch. f. exp. Path. u. Pharm., 1900, vol. 47, p. 240. 

Rosenthal, C.: Dubois' Arch., 1888, p. 1. 

Stiihlinger: Arch. f. exp. Path. u. Pharm., 1899, vol. 43, p. 167. 

ACTION OF QUININE ON HEAT PRODUCTION 
The temperature in healthy men and animals is either not dimin- 
ished at all or only very slightly, even by doses of quinine much larger 
than those which are effective in fever (Stiihlinger). In fact, after 
smaller doses the temperature not infrequently rises (J arisen, Fried- 
mann), a paradoxical effect which may be produced by other antipy- 
retics and for which no satisfactory explanation can be given. 

If the action of quinine is studied on animals in the calorimeter, 
it may be demonstrated that the fall in the body temperature is 
chiefly the result of a limitation of the heat production (Gottlieb) 
while at the same time the heat loss is augmented to a slight degree. 
The reduction of fever caused by quinine, consequently, may be 
diagrammatically represented as follows: 



s n Body temperature ,'* 
^ ^ 38° 



-37° 



Commencement of End of action 

action of quinine of quinine 

I 

Normal temp. 



Fever ( Jr | . 

niHiii 




Heat production 

— — — — Heat loss 

Fig. 60. — Antipyretic effect of quinine. Heat production diminished 
and heat loss slightly increased. 

The limitation of heat production by quinine is a primary or direct action, 
occurring even after separation of the body from the heat- regulating centres 
by section of the cord. Krehl and Matthes investigated the behavior of the 
temperature of rabbits thus prepared at the temperature of 27° C, and found 
that quinine * under such conditions caused a marked diminution in the 
amount of heat formed, while antipyrine produced no effect whatever. This 

* See, in this connection, Naunyn u. Quincke and Binz. 



QUININE 471 

indicates that antipyrine acts upon the heat economy only through the central 
nervous system, while quinine, even after the elimination of all central nervous 
influences, diminishes the metabolism of the tissues. In agreement with this, 
quinine also lessens the production of heat in surviving organs, as shown by 
Binz's observations that after section of the cervical cord no post-mortem rise 
of temperature, or only a very slight one, occurs in rabbits which have taken 
quinine, even though heat loss be prevented, although in the controls there was 
a very marked post-mortem rise. 

In a similar fashion, the addition of small amounts of quinine to the blood 
inhibits the usual formation of acid (Binz), as also the synthesis of hippuric 
acid in the surviving kidney (A. Hoffmann) , and probably other syntheses and 
decompositions (Laqueur) in the tissues are inhibited by quinine, perhaps by 
inhibition of the intracellular ferments by quinine (see Metabolism, p. 403), so 
that the heat production in the tissues is directly inhibited. 

However, it cannot be concluded that the antipyretic action of 
quinine is entirely the result of this action on the metabolism, for, 
even though the total result of the heat-producing processes is 
diminished by quinine, this diminution is always so slight that it 
could be readily compensated for by an appropriate increase of the 
heat loss if the heat-regulating mechanism were functioning normally. 
The reduction of fever produced by quinine must, consequently, have 
still another cause, which, in those cases in which its action is not a 
specific one as it is in malaria, is found in an action analogous to 
that of antipyrine, — i.e., in a sedative action on the heat-regulating 
centres. However, this central action of quinine is less powerful 
than that of the antipyrine group, a fact which is demonstrated by 
the relatively weak action of quinine in puncture hyperthermia. In 
this condition the temperature is lowered by quinine only in the 
descending portion of the temperature curve, when the hyperthermia 
already of its own accord shows a tendency to abate. It is thus evi- 
dent that quinine acts much less energetically on the function of heat 
regulation than does antipyrine (Gottlieb), and, consequently, it too 
in non-toxic doses hardly lowers the temperature in health, and exerts 
an antipyretic effect only when the heat-regulating function has be- 
come abnormally susceptible, — i.e., only in fever. 

The reduction of temperature induced by quinine results, just as 
in normal defervescence, from augmentation of the heat output and 
diminution of its production. Quinine consequently, as a result of 
its slight action on the heat-regulating centres, also aids spontaneous 
defervescence, which effect is aided by the direct diminution of heat 
production resulting from its action on the metabolism, and, as quinine 
primarily limits proteid metabolism, it aids the organism in con- 
serving its most valuable material. 

However, by no means all fevers may be successfully combated 
with moderate doses of quinine. The more marked effect of quinine 
in certain infectious fevers, — i.e., in typhoid (Erb)* — is perhaps duo 
to a direct action on the cause of the fever, resembling its specific 
action on the malarial organisms (see Etiotropic Agents, p. 527). 

* [This is certainly doubtful.— TS.] 



472 PHARMACOLOGY OF HEAT REGULATION 

BIBLIOGRAPHY 

Binz: Virchow's Arch., 1870, vol. 51, p. 152. 

Binz: Arch. f. exp. Bath. u. Pharm. 1S73, vol. 1, p. 18. 

Erb. YV. : Therapie d. Gegemvart, January, 1901. 

Friedmann: lnaug.-Diss., Erlangen, 1890. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1S90, vol. 26, p. 419. 

Gottlieb: Arch. f. exp. Path. u. Pharm., 1891, vol. 28, p. 107. 

Hoffmann: Arch. f. exp. Path. u. Pharm., 1877, vol. 7, p. 233. 

Jansen: lnaug.-Diss., Dorpat, 1S72. 

Laqueur: Arch. f. exp. Path. u. Pharm., 1900, vol. 55, p. 240. 

Naunyn u. Quincke: Arch. f. Anat. u. Physiol., 1869, p. 571. 

Stiihlinger: Arch. f. exp. Path. u. Pharm., 1899, vol. 43. 

THE SALICYLATES 

Salicylic acid apparently occupies a position between quinine and 
the antipyrine group. In common with quinine, it appears to have 
the property of acting directly on the cause of the fever in acute 
articular rheumatism and in many other infections, and, like it, 
salicylic acid too has comparatively little effect on puncture hyper- 
thermia. In these particulars it stands close to quinine and in a 
certain opposition to the antipyretics which act purely symptomatic 
cally. 

On the other hand, salicylic acid stands closer to antipyrine in 
respect to the manner in which it lowers the temperature in fever. 
Particularly in those conditions in which it acts only on the fever 
and not on the cause of the disease, it not only does not lessen 
proteid metabolism but, on the contrary, very markedly increases it 
(Kumagawa, Virchow, Salome, etc.). The reduction of febrile tem- 
perature by salicylic, acid is due, as is the case with the antipyrine 
group, to an augmentation of heat loss, particularly as a result of 
sweating, and the later rise of the temperature may often actually 
be accompanied by a chill. However, the behavior of the heat 
economy of the body under the influence of the salicylates has not 
been sufficiently studied to permit of a closer knowledge of its 
details. 

Acetyl-salicylic acid, introduced by Dreser under the name of 
aspirin, appears to stand much nearer to the antipyrine group. It 
lowers the temperature caused by the heat puncture much more 
strongly, and is consequently more effective as a purely symptomatic 
antipyretic than is salicylate of soda (Bondi u. Katz). Although 
aspirin is excreted only after being decomposed, it may be absorbed 
without undergoing decomposition, for this occurs but slowly in the 
intestine. Consequently, before it is decomposed with the formation 
of salicylic acid by the ferments of the tissues, it may be differently 
distributed and produce other actions than its mother substance. 

BIBLIOGRAPHY 

Bondi u. Katz: Ztsclir. f. klin. Med., 1910, vol. 72, p. 177. 
Dreser: Pfiuger's Arch., 1899, vol. 76. 
Kumagawa: Virchow's Arch., 1888, vol. 113. 
Salome: Wien. med. Jahrbiicher, lssr.. 
Virchow, C: Zeitschr. f. physiol. Chemie, 1881, vol. 6. 



SALICYLATES AND OTHER ANTIPYRETICS 473 

OTHEE ANTIPYRETIC AGENTS 

Many other substances also possess the power of depress' ng the 
temperature. In general this power is a characteristic of many 
benzol derivatives, — for example, of carbolic acid, which may serve 
as a prototype of the aromatic antiseptics (Harnack). While the 
antipyretic action of phenol may not be utilized therapeutically be- 
cause of its other toxic actions, and while other substances chemically 
closely resembling carbolic acid (hydroquinine, etc.) are too poisonous 
and often produce collapse, various aniline and paramidophenol 
derivatives, formed by introduction of acids into their molecules, are 
comparatively non-toxic antipyretics. 

As a part of their general narcotic action, moreover, many nar- 
cotics of the alcohol group, in particular alcohol itself, exert a seda- 
tive action on the heat-regulating centres, and in large doses paralyze 
them, so that collapse with a marked fall of body temperature 
develops. 

On the other hand, it has long been known that the powerful central 
stimulant camphor, when given in large doses, lowers the temperature in fever 
(Hoffmann) . Harnack and his collaborators have also found that other con- 
vulsants, particularly picrotoxin and santonin, may also lower the body tem- 
perature independently of any convulsions which they may cause. The same 
is true for aniline, which also possesses a convulsant action (ScJmchardt). 
Moreover, the combination of santonin or picrotoxin with chloral, amylene 
hydrate, ether, or chloroform, etc., which of themselves possess but slight 
power to lower temperature, produces a tremendous fall in the temperature, 
which is much larger than is accounted for by the sum of the effects of each 
of these components. Evidently, while both of these groups of antithermic drugs 
act on the heat-regulating centres, their points of action are certainly different, 
as is evidenced by the different behavior of the temperature when cocaine is 
administered to animals in which the temperature has been lowered by some 
member of one or the other of these groups (Harnack u. Schwedmann) . 

BIBLIOGRAPHY 

Harnack, E.: Miinchn. med. Woch., 1910, No. 37. 

Harnack: Ztechr. f. klin. Med.. 1896, vols. 24 and 25. 

Harnack: Arch. f. exp. Path. u. Pharm., 1890, vol. 38; 1891, vol. 39; 1892, vol 

45; 1893, vol.49. 
Harnack u. Schwedmann: Arch. f. exp. Path. u. Pharm., 1897, vol. 40, p. 151. 
Hoffmann: [naug.-Disa., Dorpat, 1866. 
Schuchardt: Arch. d. Pharmazie, 1861. 

THERAPEUTIC EMPLOYMENT OF THE ANTIPYRETICS 
Up to a few years ago physicians believed that it was necessary 
to give antipyretics in the presence of any marked febrile augmen- 
tation of the temperature. This routine endeavor to combat fever 
was due to theoretical conceptions which, ever since the middle of the 
Last century, have led to the assumption that the anatomical alter- 
ations observed in the parenchymatous organs after severe infection 
were produced by long-continued high temperature. (In this con- 
nection see Krehl.) Hence the fear of fever. The introduction of 
the modern antipyretics, which permit the prompt reduction of tem- 
perature without producing harmful side effects, was a welcome aid 



474 PHARMACOLOGY OF HEAT REGULATION 

in this endeavor to combat fever, for by their use it was possible 
to cause even such a disease as typhoid to run its course without 
fever. 

However, it was just this energetic employment of antipyresis 
which has taught us that by no means all the supposed dangers of 
fever are due to the augmentation of the temperature as such, and 
to-day, as a result of the experimental investigations of Naunyn, 
Pfluger, Finkler, TJnverriclit, and others, it is known that these 
pathological changes are not the results of the increased temperatures, 
but that they are a coordinate effect, which, like the alterations 
in the function of heat regulation, is dependent upon the intoxication 
produced by the specific infectious poisons. 

The augmentation of the temperature is a reaction of the central 
nervous system to its invasion by these poisons, and is thus a symptom 
of which we cannot decide a priori whether it be harmful or useful 
to the organism. In more recent times the conviction has gained 
ground that fever as such is harmless, and we have been more and 
more inclined to the view — which, by the way, is hundreds of years 
old — that the rise of temperature represents a curative effort of 
nature, — i.e., that it is a defensive reaction of the diseased organism, 
which is useful to it in its struggle with the cause of the disease and 
of the fever. In many particulars present investigations support this 
view, for augmentation of the body temperature by overheating 
(Filehne, Walther, Rovighi) or by heat puncture {Loewy u. Richter) 
appears to exert a favorable influence on the course of experimentally 
induced infections. 

In what fashion such high temperatures produce their favorable 
effects is not entirely clear, but it is less probably due to a direct 
effect upon the growth and virulence of the bacteria than to the 
effect of the increased temperature in augmenting combustive pro- 
cesses and in producing a more active formation of the various pro- 
tective substances (East, Krehl, Roily, Meltzer, Liidke). Thus, for 
example, it has been shown that, when the formation of antibodies had 
already become less active, the amount of these substances in the 
blood of infected rabbits increased again if their temperature was 
raised by heat puncture (Aronsohn u. Citron). 

Consequently, it is not the augmentation of temperature as such 
which should be combated, but only certain accompanying phenomena. 
Among these it is certain that the accelerated action of the heart, 
the dyspnoea, and at least a portion of the augmentation of metabolic 
processes are to be considered as due to the abnormal temperature, 
and, in case of excessive hyperpyrexia, these may become distinctly 
dangerous to the patient. Consequently an excessive degree of an 
otherwise useful reaction must be combated by antipyretics. More- 
over, various other symptoms present in infectious diseases — above 
all, the restlessness, headache, anorexia, etc., of the febrile patient — 



THERAPEUTIC ACTIONS OF ANTIPYRETICS 475 

are favorably influenced by the canning action of the antipyretics. 
Consequently, one uses the antipyretics more to secure their sedative 
effects than to lower the temperature, just as to-day one uses hydro- 
therapy in fever rather for its favorable effect on the sensorium and 
the circulation and respiration than for its power of lowering tem- 
perature. Consequently, it is the pharmacological property of the 
antipyretics of acting as " fever narcotics" winch is the chief factor 
in their therapeutic value. In addition to this, we cannot deny that 
in infectious fevers they may exert other unknown actions which 
would account for their favorable influence on various symptoms. 

Analgesic and Hypnotic Actions. — The narcotic mild "morphine- 
like" action on the algesic centres comes into play when they are 
used in the presence of neuralgic pains of different kinds. It is 
possible that the almost specific action of these drugs in neuralgias is 
in part due to an increased determination of the blood to the 
periphery of the body. In headache their power of relieving spasm 
of the cerebral arteries may play a role, for Wiechowski has found 
that a very large majority of the analgesics of the group dilate the 
cerebral vessels as well as the cutaneous ones, and such spasmodic 
contraction of the cerebral vessels appears to occur in many patho- 
logical conditions in which headache is a frequent symptom, — for 
example, in unemia. It is, therefore, not improbable that the aboli- 
tion of cerebral vascular spasm is responsible for the relief of the head- 
ache which often follows the use of the antipyretics in such cases. 

BIBLIOGRAPHY 

Aronsohn u. Citron: Ztschr. f. exp. Path. u. Therap., 1910, vol. 8. 

Fileline: Journ. of Physiol., 1894, vol. 17, p. 21. 

Finkler: Pfliiger's Arch., 18S2, vol. 29, p. 235. 

Kast: Kongr. f. inn. Med., 1896, p. 37. 

Krehl: In Lubarsch-Ostertag, Ergebnisse d. allg. Path., 189G, vol. 3, p. 407. 

Krehl: Pathol. Physiol., Leipzig, 1906, p. 493. 

Loewy u. Richter: Virchow's Arch., 1896, vol. 145, p. 49. 

Liidke: Deut. Arch. f. klin. Med., 1909, vol. 94. 

Naunyn: Arch. f. exp. Path. u. Pharm., 1884, vol. 18, p. 49. 

Pfltiger: Pfliiger's Arch., 1877, vol. 14, p. 502. 

Roily u. Meltzer: Deut. Arch. f. Klin. Med., 1908, vol. 94. 

Rovighi: Prager med. Woch., 1892. 

T'nvcrricht: Volkmann's Vortriige, No. 159. 

Walther: Zbl. f. Bakteriol., 1891, p. 178. 

Wiechowski: Arch. f. exp. Path. u. Pharm., 1902, vol. 48, p. 376; 1905, vol. 52, 

p. 389. 

QUININE 

Cinchona bark is obtained from different species of cinchona 
which are natives of the highlands of western South America. Long 
used by the natives in malaria and other fevers, after the discovery 
of South America it was brought to Europe under the name of 
Jesuit's powder, and became known to the medical world about the 
end of the 17th oentury. 

While formerly obtained from various wild varieties of the cin- 



476 PHARMACOLOGY OF HEAT REGULATION 

chona tree, it is now chiefly obtained from a dwarf variety, Cinchona 
succirubra, which is cultivated on a large scale in Java and the East 
Indies. This bark contains more than 20 alkaloids, the so-called 
cinchona bases, of which, besides quinine, only quinidine, cinchonine, 
and chinchonidine need be mentioned. The official bark must contain 
5 per cent, of alkaloids. 

While the bark is still much used in the form of extracts and 
tinctures as a bitter (see p. 167) and tonic (see p. 404), in the 
treatment of fever it has been entirely replaced by quinine, first 
prepared by Pelletier and Caventou in 1820. 

Quinine, C 20 H„ 4 N 2 O 2 , occurs in the bark in combination with 
quinaic acid and quinotannic acids. Its structural formula is 
probably as follows: 



CH 3 



H 

C C-C,oH 15 OHN 



,CH 



C N 
H 

Of the various water-soluble and intensely bitter salts, the 
hydrochloride is the most useful. It is soluble in 30 parts of water, 
but the addition of urea, urethan, or antipyrine renders it soluble in 
equal parts of water. The sulphate is soluble in 800 parts of water, 
and the bisulphate in 12 parts, its solutions having an acid reaction. 

Various insoluble preparations are more or less used, because, 
being insoluble, they are also tasteless or almost so. It should be 
remembered, however, that their insolubility renders their absorption 
slow and uncertain. Of these the more widely used ones are 

• XXC2H5 
quinine tannate, equinine (quinine ethyl carbonate), C0\ 

X)C 2 oH,3N 2 

and aristochin (diquinine carbonic ester), CO<Q , which, 

^OCaoHzsNaO 

on account of their lack of taste, are frequently administered to 
children. 

Quinine is unequalled by any other substance as a specific for 
malaria, and is also used in the treatment of neuralgia, whooping- 
cough, and other conditions. As an antipyretic in other infectious 
diseases, it possesses advantages only in those (typhoid, septicemia, 
influenza) in which, with more or less justification,* specific effects may 
be attributed to it, or in cases where its long-continued use is indi- 
cated in order that its conservative action on the proteid metabolism 
may be of advantage. These advantages are, however, counter- 
balanced by its weaker antipyretic powers and by the disagreeable 

* See footnote, p. ,471. 



QUININE AND ANTIPYRINE GROUP 477 

"side actions" of larger doses, particularly on the central nervous 
system, even doses of 1.0 gm. at times causing cinchonism, with its 
symptoms of tinnitus, deafness, vertigo, headache, and vomiting. It 
may also act unfavorably on the alimentary canal, the continued use 
of even small doses occasionally causing various types of indigestion. 
Skin eruptions also not infrequently follow the administration of 
quinine. Toxic doses cause more or less persistent deafness and 
serious disturbances of the vision, even permanent blindness, and 
very large doses may cause stupor, coma, and collapse as a result of 
depression of the central nervous system and of the heart. 

While the greater portion of quinine is combusted or otherwise 
decomposed in the organism (Nishi), a portion is excreted unchanged 
by the kidneys, the urine acquiring an emerald-green color on the 
addition of chlorine water and ammonia, a reaction characteristic of 
quinine solutions. 

BIBLIOGRAPHY 
Nishi: Arch. f. exp. Path. u. Pharm., 1909, vol. 60, p. 312. 

ANTIPYRINE GROUP 
In the endeavor to obtain substitutes for quinine, the start was 
made by searching for the active nucleus of quinine. 

While quinoline, 

H H 
C C 



HC/ V \CH 



HC\ A /CH, 

N 
H 

one of its decomposition products, acts as an antipyretic and powerful narcotic, 
it so readily causes collapse that it could not be used in practice. However, 
in 1883, by the introduction of side chains into quinoline, the first useful 
synthetic antipyretics, kairine and thallm, were obtained; but these also acted 
too violently, for, although after their administration the temperature falls 
rapidly with profuse sweating, it rises again after a comparatively short 
time, this rise being not infrequently accompanied by a chill. 

In 1884 Knorr prepared and recognized the antipyretic powers of 
antipyrine, a pyrazolon derivative, and in 1887 the therapeutic properties 
of acetanilide were discovered. While the antipyretic action of its mother 
substance, aniline, bad been recognized by Schuchardt in 18G1, this discovery had 
remained unnoticed. Although aniline itself is powerfully toxic, the discovery of 
acetanilide indicated that among its derivatives and those of the closely related 
paramidophenol there were certain relatively non-toxic and promptly acting 
antipyretics. 

The antipyretics belonging to this pharmacological group may, 
from a chemical point of view, be divided into the aniline and 
paramidophenol derivatives and the substances of the pyrazolon 
group. 

BIBLIOGRAPHY 
Schuchardl : Arch. d. Pharm., 18G1. 



478 PHARMACOLOGY OF HEAT REGULATION 

I. ANILINE AND PARAMIDOPHENOL DERIVATIVES 
Although these mother substances are powerfully toxic to nervous 
cells, and although in larger doses they cause the formation of 
methcTmoglobin, their toxicity may be diminished by the introduction 
of various side chains. Paramidophenol is less toxic and more anti- 
pyretic than the ortho- and meta-modifications, which are less power- 
ful antipyretics and at the same time are more destructive to the 
blood. 

After large doses of these substances the urine often becomes dark colored 
and, on account of the presence in it of paramidophenol, gives the indophenol 
reaction — i.e., on the addition of hydrochloric acid and sodium nitrate followed 
by an alkaline solution of naphthol and then by NaOH, acquires a red color, 
which on acidification changes to violet. 

0-C 2 H 6 

H OH HC A CH 

c 



CH HC,/ \.CH 

CH HC'\ Am 



Hcl/ 



HC\ /CH „ HC\ /CH 

HC X/ CH ><1n/ H Y N\ 

C-NH, XX) CH, NH 2 X CO.CH 3 

Aniline. Acetanilide. Paramidophenol. Phenacetin. 

Acetanilide (antifebrin) , obtained from aniline by replacing one 
hydrogen atom of the amido group by an acetyl radical, occurs as 
a crystalline bitter substance, soluble in 230 parts of water. It is 
a prompt and powerful antipyretic and analgesic, of which the dose 
is 0.2 to 0.3 gm. per dose. In former times, as a result of exceeding 
the proper dosage, numerous cases of poisoning occurred, which were 
characterized by cyanosis of the face and blueness of the hands and 
fingernails, effects of the formation of niethasmoglobin and the de- 
struction of the blood-vessels (Mutter). In more serious poisoning 
collapse also frequently occurred. 

In the body, the nucleus of acetanilide undergoes oxidation, and 
it is excreted chiefly in conjunction with sulphuric and glycuronic 
acids as acetylparamidophenol (Mutter, Morner). 

Phenacetin, acetphenetidin, is a paramidophenol, in which an 
ethyl radical has been introduced into the hydroxyl group and an 
acetyl radical into the amido group, and may, therefore, be termed an 
oxyethylacetanilide. It is a tasteless crystalline powder, which is 
very insoluble in water and more active [? Tr.] and less toxic than 
acetanilide. Doses of 0.25 gm. produce some antipyretic effects, while 
after 0.5 to 0.75 gm. the antipyretic effect is apparent after 30 
minutes and lasts for 6 to 8 hours, usually unaccompanied by dis- 
agreeable side actions. In doses of 0.3 to 0.7 gm. it is a useful 
analgesic and sedative. After larger doses, such as 1.0 gm. per dose 
or 3.0 gm. per diem, cyanosis similar to that caused by acetanilide 
has been observed, but it rarely or never causes severe collapse. 



ANTIPYRINE GROUP 479 

Lactophenine, lactyl-para-phenetidin, is a phenacetin in which the acetyl 
radical has been replaced by the lactic acid radical. It is more soluble than 
phenacetin and has proven a useful antipyretic, possessing also considerable 
sedative powers. The maximum dose is 0.5 gm. per dose, 3.0 gm. per diem. 

BIBLIOGRAPHY 

Jaffe u. Hilbert: Ztschr. f. physiol. Chemie, 1888, vol. 12, p. 295. 
Morner: Ztschr. f. physiol. Chemie, vol. 13, p. 12. 
Miiller, Fr.: Deut. med. Woch., 1887, No. 2. 

II. PYRAZOLON DERIVATIVES 
Antipyrine, phenyldimethylpyrazolon, is a derivative of pyra- 
zolon, its constitution being illustrated by the following formula: 

HC_ CH H 2 C CH (CH 3 )2C CH 

HC1 )CH = C! 



Pyrrol: N Pyrazolon: N Antipyrine: N 

I H I 

H C 6 H 6 

It is a colorless crystalline powder, with a neutral reaction and a very 
slightly bitter taste, which is soluble in equal parts of water. With ferric 
chloride it gives, even in very dilute solutions, a blood-red color, and with 
sodium nitrite an intense green color, due to the formation of nitroso-antipyrine. 
Following its administration, the urine is usually dark colored and acquires a 
reddish-purple color on the addition of ferric chloride. A portion is excreted 
unchanged, but the greater portion is excreted in conjugation with glycuronic 
acid as oxyantipyrine. 

In doses of 0.4 to 0.8 gm. antipyrine is a certainly acting but 
rather mild antipyretic, the temperature usually falling during the 
course of 3 to 4 hours, accompanied by sweating, and rising again 
gradually. Alarming collapse, such as results from some of the more 
violently acting antipyretics, is observed after antipyrine no more 
frequently than with phenacetin. It is also very much used as a 
sedative and analgesic, the maximal dose being 1.0 gm. per dose and 
3.0 gm. per diem. 

Although even doses of 2.0 gm. very seldom cause any disagreeable 
effects, still certain individuals exhibit a striking idiosyncrasy to an- 
tipyrine. The most common undesirable effect is the occurrence of 
skin eruptions, which, while disagreeable, are not dangerous. It is 
only in the presence of idiosyncrasy that severer cutaneous manifesta- 
tions occur, such as inflammatory swelling of the skin of the face 
and of the genital organs, as also symptoms of irritation of the 
mucous membranes, such as conjunctivitis, pharyngitis, laryngitis, 
etc., and occasionally pronounced disturbances of the stomach (Falk). 

Miffraininr is not a chemical substance, but a mixture of antipyrine 85 
parts, caffeine '■* parts, and citric acid <» parts. 

S<ilip!/ri)ir, plionyldimetliylpyrazolon salicylate, is a coarse crystalline powder, 
soluble with difficulty in water, <>f wliich the dose is 0.5 to 1.0 gm. 



480 PHARMACOLOGY OF HEAT REGULATION 

Pyramidon, dimethylamido antipyrine, is a crystalline powder, 
only slightly soluble in water and almost tasteless. Its actions are 
similar to those of antipyrine, but it is 3 or 4 times as powerful 
[ ? Tr.], so that its dosage is correspondingly smaller (0.25 to 0.3 gm.). 
[Pyramidon, besides being an antipyretic and analgesic, is apparently 
also a fairly powerful hypnotic. — Tr.] After its administration, 
antipyryl urea and a red coloring substance, rubazonic acid, appear 
in the urine (JafJ'c). 

BIBLIOGRAPHY 

Falk: Therap. Monatsh., 1890, p. 97. 

Jaffe: Berichte d. deut. chem. Ges., vol. 34, 1901, p. 2737. 

III. SALICYLIC ACID GROUP 

Although free salicylic acid is antiseptic and locally very irritant, 
sodium salicylate lacks these properties. 

Sodium salicylate, a white hygroscopic powder, soluble in equal 
parts of water, acts in doses of 0.5 to 1.0 gm. as an antipyretic, but 
this action is not so elective as is the case with the above-mentioned 
drugs, and, if the dose be too large, symptoms of excitation of certain 
parts of the central nervous system and disturbances of the digestion 
readily appear. As undesirable side effects, it may cause dyspnoea 
and symptoms like those of einehonism, — viz., deafness, tinnitus, 
vertigo, headache, and confusion, — and, if there be a pronounced fall 
of temperature, it relatively often causes collapse. 

Those compounds of sodium salicylate, such as salol (phenyl 
salicylate), from which it is gradually set free in the intestine, cause 
these disagreeable side effects to a slighter degree, inasmuch as less 
salicylic acid reaches the circulation at one time. This is also true 
for aspirin, acetyl salicylic acid (see p. 472), at present widely used 
in place of the salicylate of socla. The antipyretic effects of aspirin 
also appear to be greater than those of salicylic acid, even doses of 0.25 
gm. producing pronounced antipyresis in typhoid fever (Bondi). 

BIBLIOGRAPHY 
Bondi: Ztschr. f. klin. Med., 1911, vol. 72, p. 171. 



CHAPTER XVI 
PHARMACOLOGY OF INFLAMMATION 
NATURE OF INFLAMMATION 

In its biological significance, inflammation may be looked upon as a 
reaction of damaged tissues, by means of which the damage is limited 
and such tissues as may be destroyed are removed and replaced. 
The essential process in this reaction is an alteration of the function 
of the vessel walls, affecting not only the smaller arterioles and veins 
but also the capillaries, as a result of which the vessels dilate, losing 
their tone and becoming permeable for both the plasma and the red 
and white blood-cells, so that transudation occurs (Klemensiewitz) . 

The first effect is an active hyperemia, causing heat and red- 
ness, and the second an increased transudation into the perivascular 
and interstitial lymph-spaces, causing oedema or swelling. This 
oedema increases the tension in the tissues, and consequently causes 
stasis of the blood and stretching or twisting of the nerves, with 
tenderness and pain. Finally, the leucocytes and to a less extent the 
erythrocytes leave the inflamed vessels in large numbers, which leads 
to infiltration of the tissues, phagocytosis, and formation of pus, and 
also to cytolysis by the pus-cells, with a resulting dissolution and 
regeneration of tissues. For our purposes it is not necessary to go 
more deeply into these complex processes of inflammation; but it 
should be strongly emphasized that in general the reaction of inflam- 
mation is a useful process, and one necessary for the cure of the 
patient and for replacement of destroyed tissues, which, however, can 
itself work harm to the organism not only by causing violent pain 
but also by causing temporary or permanent functional disturbances, 
as, for instance, by the formation of large exudates or cicatrices or 
as a result of destruction of important tissues. 

From such consideration it is clear that it will often be extremely 
desirable to be able to control inflammation either by stimulating 
or moderating its activity. Hence arises the demand for agents 
which stimulate and those which inhibit inflammation. 

THE EXCITATION OR STIMULATION OF INFLAMMATION 

The vasomotor disturbances which cause or initiate inflammation 
may be induced indirectly through the vasomotor nerves, or directly 
by the action of chemical substances on the vessels themselves. That 
inflammatory vascular disturbances, with .-ill their sequela?, may re- 
sult from nervous influences, is proven by Ihe occurrence of the 
different forms of herpes as the resull of pathological processes in 
the spinal ganglia, as also by the occurrence of circumscribed hyper- 
31 481 



482 PHARMACOLOGY OF INFLAMMATION 

aemia or of vesicles, bulla?, etc., as a result of suggestion {Heller u. 
Schultz). Such lesions are in all probability always due to a peculiar 
primary stimulation of the vasodilator nerves, which causes first an 
active hyperemia and later increased permeability of the vessels, 
leading to transudation, etc. 

It is difficult to refrain from assuming in such cases that certain trophic 
functions of the vasomotor nerves, or perhaps specific trophic nerves, which re- 
spond only to certain adequate stimuli, also play a role in causing the inflam- 
matory reaction, for inflammation never results from simple vasodilatation, such 
as follows experimental stimulation of vasodilator nerves in the skin or that 
caused by the functional activity of the organs. 

In this connection it is of interest that these vasodilator nerves 
which accompany the spinal and some of the cranial nerves — e.g., 
the trigeminus — appear to be identical with the sensory nerves which 
are interrupted in the synapses of the spinal ganglia (Bayliss). If 
this be actually so, the sensory nerves must transmit not only 
centripetal sensory impulses but also centrifugal vasodilator impulses, 
and, consequently, it must be assumed that their peripheral termina- 
tions are dichotomous, one twig passing to the cutaneous sensory- 
corpuscles and the other into the smaller vessels. One is consequently 
tempted to assume the possibility of the passage of stimuli over a 
short path from algesic points to the smaller vessels, in analogy with 
an axon reflex. This assumption would explain why every painful 
irritation of the skin causes almost immediately a local active hyper- 
emia, the first stage of inflammation, and why, on the other hand, 
when the painful irritation of the skin is prevented, either by 
analgesic drugs or by cold, hyperemia does not develop or is dimin- 
ished, and with it also -all other signs of inflammation (Spiess).. 

Bruce's studies indicate that these assumptions are well founded, for they 
show that, when inflammation is due to cutaneous irritation, it occurs even 
after section of the peripheral nerve-trunks, indicating that the reflex occurs 
independently of the central nervous system. Moreover, if the sensory nerve- 
endings be paralyzed by cocaine, alypin, or similarly acting drugs, irritation, 
which ordinarily causes inflammation, such as that caused by cantharidin when 
applied to the conjunctiva of a rabbit, produces no inflammatory reaction so 
long as the anaesthesia lasts, or none at all if the sensory nerve-endings have 
degenerated, as occurs within about eight days after section of the correspond- 
ing sensory nerves. 

Consequently, drugs or other agents which when locally applied 
first cause more or less severe pain and resulting redness and inflam- 
mation are to be grouped together as indirect irritants. These cor- 
respond in general to those drugs or measures which are ordinarily 
termed 

CUTANEOUS IRRITANTS OR RUBEFACIENTS 

and include heat and numerous substances, particularly such as are 
volatile and readily penetrate the epidermis. Among the most im- 
portant are oil of mustard, turpentine, chloroform, acids, ammonia, 
camphor, and iodine. The prolonged action of all these drugs and 






EXCITATION OF INFLAMMATION 483 

of heat also, or their use in strong concentrations, besides irritating 
the sensory nerve-endings, can injure the tissues and can either cause 
inflammatory vasomotor changes or cause the death of various tissue 
cells. In such actions they resemble the members of the group of 

SUBSTANCES WHICH DIRECTLY EXCITE INFLAMMATION 

(a) Specific vascular poisons, substances which, without causing 
any destruction or necrosis of the tissues, act only on the vessels, per- 
haps also on the lymphatics, dilating them and rendering them abnor- 
mally permeable. These are certain toxic substances, probably proteid 
in their nature, which belong to the group of the so-called toxins. 
Among these may be mentioned tuberculin (Pirquet), diphtheria 
toxin (Bingel), abrin and ricin, the toxic substances of the pollen 
of certain graminacese, the hay-fever toxin (Wolf -Eisner), snake 
venoms, cantharidin, the toxic substances of the poison-ivy, Ehus 
toxicodendron (Ford, Pfaff), and of the primula, Daphne mezereum, 
the toxic substance in the bee's sting (Langer), and the Kalahari 
arrow-poison (Starcke). These substances all cause active hyper- 
gemia and serous infiltration of the tissues. Those which are able 
to penetrate the skin when applied to it cause papules or vesicles 
containing leucocytes and often large numbers of red cells. 

These substances possess the common characteristic that certain 
individuals or species of animals are entirely or relatively immune 
to them, their action being dependent on a specific disposition of the 
individual or species, the nature of which is still almost entirely 
unknown. Such disposition may be either positive or negative, mani- 
festing itself as a specific susceptibility or a specific insusceptibility 
of the organism to a certain poison. In many cases this disposition 
is changeable, but in others it is constant. 

Tuberculin excites a distinct cutaneous reaction only in individuals who 
are or who have been infected with tuberculosis, and a decidedly more pronounced 
reaction in the tubercular tissues than in the non-tubercular ones. The same 
holds good f<»r reactions to other toxins and heterologous sera (v. Pirquet). 

Cantharidin also acts more strongly on tubercular lesions than on normal 
tissues. On the other hand, the tissues of many species of animals (hedgehog, 
chicken, frog) are in a high degree immune to it. Contact with poison-ivy 
and the primula obconica (Wechselmwm) causes erythema and vesication only 
in BUflceptible individuals. Snake venom, abrin, ricin, and poison-ivy are harm- 
less to the skin of cold-blooded animals, but on human skin they are very 
poisonous, snake venom only when the epithelium has been injured, but abrin 
and ricin through the uninjured cutis. However, in man repeated mild poison- 
ing with them leads to an immunity, which probably is entirely distinct from 
the natural immunity of the cold-blooded animals. 

(b) Caustic and Necrotizing Agents. — A very large number of 
substances possess in common the power of killing ;i]l living proto- 
plasm alike. These are either substances causing instantaneous des- 
truction — as is the case with trauma, glowing heat, and corrosives of 
all kinds, such as concentrated acids and alkalies — or substances, such 



484 PHARMACOLOGY OF INFLAMMATION 

as arsenic, which cause necrosis by more delicate but nonreversible and 
therefore progressive molecular actions which gradually cause the 
death of the tissues. 

Whether rapid or slow, the death of the tissue cells under all 
conditions causes a chemical decomposition of protoplasm, with a 
resulting formation of decomposition products, just as occurs in the 
fermentative post-mortem autolysis of organs. These decomposition 
products possess in a high degree the power of exciting inflamma- 
tion, — i.e., they produce the essential vascular changes and chemo- 
tactic assemblage of leucocytes. Apparently they irritate or render 
more irritable the algesic nerves, and perhaps they also furnish a 
stimulus for the growth of regenerating tissues. 

The augmentation of the susceptibility to pain by inflammatory products 
is especially strikingly demonstrated in the visceral peritoneum, whose algesic 
nervous mechanism ordinarily responds only to stimuli resulting from extreme 
distention, but which in peritonitis responds to every slightest mechanical — and 
presumably also to every chemical — irritation. 

BIBLIOGRAPHY 

Bayliss: Journ. of Physiol., 1900, vol. 26, p. 173. 

Bingel: Miinchn. med. Woch., 1909, No. 26. 

Bruce, Alex. N.: Arch. f. exp. Path. u. Pharm., 1900, vol. 63, p. 424. 

Ellinger: Arch. f. exp. Path. u. Pharm., 190S, vol. 58. 

Ford: Journ. of Infect. Diseases, Chicago. 1907, vol. 4, p. 541. 

Heller u. Schultz: Hypnotisch erzeugte Blasenbildung, Miinchn. med. Woch., 

1909, No. 41. 
Klemensiewitz: Jena, 1908. 

Langer: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 381. 
Langer: Arch, intern, de Pharmacodvn., 1899, vol. 6, p. 181. 
Pfaff : Journ. of exp. Med., 1889. 

v. Pirquet: Ergebn. d. inn. Med., 1908, A 7 ol. 1, p. 420, literature. 
V. Recklinghausen: Hdb. d. allg. Pathol., Stuttgart, 1883, p. 218. 
Spiess: Miinchn. med. Woch., 1906. 

Starcke: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 428. 
Wechselmann: Monatsh. f. pr. Dermatol., 1902, vol. 35. 
Wolf-Eisner: Das Heufieber, Miinchen, 1900. 

CLASSIFICATION 
Substances and agents which excite inflammation may consequently 
be divided into three groups, which, however, cannot be sharply 
differentiated from each other. 

1. Painful cutaneous irritants, the rubefacients. 

2. Vascular poisons, the vesicants and pustulants, which, when 
applied to the skin, cause vesication and pustulation, and when ap- 
plied to the mucous membranes cause hyperemia, oedema, and forma- 
tion of pus. 

3. Cytotoxic agents, caustic and necrotizing agents. 

THERAPEUTIC EMPLOYMENT AND MODE OF ACTION 
Formerly these agents were used locally as derivativas and 
epispastics, with the idea that by their action on the surface a deep- 



COUNTERIRRITANTS 485 

seated inflammation could be brought to the surface. At that time, 
however, there was no satisfactory explanation or knowledge of the 
manner in which counterirritation produced its beneficial results. 

To-day their mode of action is no longer so incomprehensible, 
since Bier has shown that passive hyperemia of an organ — i.e., a 
hyperemia resulting from primary vasodilation — is a condition 
of essential moment for the protective reactions of inflammation and 
also of importance for the relief of pain. It has also been shown 
that irritation of the skin causes hyperemia not only superficially 
but, according to its severity, in more or less deep-lying as well as 
in more or less distant parts, .and even in organs which are in no way 
directly connected with the skin; for instance, in the thoracic and 
abdominal viscera and in the dura, in which latter cases it is evident 
that the hyperemia must be reflexly induced. Head has shown that 
inflammation of the different viscera often causes a hyperesthesia 
or hyperalgesia of those portions of the skin which are innervated 
from the same segments of the cord to which the sensory nerves 
of the viscera in question pass, and that there is a definite reflex 
sensory relationship between the viscera and the skin. It would, 
therefore, appear more than probable that an irritation from without 
may produce effects on the related viscera and cause a hyperemia, 
and, as a matter of fact, it is possible experimentally to demonstrate 
that this is the case. 

It is thus evident that the term derivative as used in connection 
with the counterirritants is a misnomer, for they do not deprive the 
organs of blood, but, on the contrary, augment their blood supply, and 
thus under certain conditions may exert a favorable influence on the 
process of healing or repair. 

In addition, sensory irritation, according to its severity, reflexly 
stimulates or depresses (inhibits) the circulation and the respiration. 
Thus, the respiration is stimulated by mechanical or chemical stimula- 
tion of the trifacial nerve-endings in the nasal mucosa, or by cold 
douching of the neck or breast and by other similar procedures (see 
p. 341). Very violent cutaneous irritation, such as that which 
may be produced by mustard or cantharides, diminishes the respira- 
tory exchange in rabbits, but thus far this question has not been 
sufficiently investigated in man (Mayer). 

Mild cutaneous irritation appears to produce an opposite effect, 
increasing both the depth of respiration and the respiratory ex- 
change (Rubncr, W inter nit z, Loewy u. Midler, Matthcs). 

The vasoconstrictor centres are stimulated even by weak sensory 
stimuli, and the vasodilator and vagus centres by powerful ones. 
While these reflexes, although of great importance both for physiology 
and therapeutics, cannot be discussed further in this place, it should 
be mentioned that they play an important role in physical therapy, 
particularly in hydro- and electrotherapy (Mutter). 



486 PHARMACOLOGY OF INFLAMMATION 

BIBLIOGRAPHY 

Bier: Hyperiimie als Heilmittel, Leipzig, 1006. 

Head: Die Sensibilitiltssturungen d. Haut bei Visceralerkrankungen, Berlin, 

1898. 
Loewy u. Midler: Pfliiger's Arch., 1904, vol. 103. 

Mattnes: v. Noorden's Handb. d. Path. d. Stoffwechsels, 1907, vol. 2. 
Mayer, L.: Trav. Solvav, 1901. vol. 4, p. 73. 
Miiller, O.: Med. Klinik, 1909, No. 15. 
Rubner: Arch. f. Hvg., 1903. vol. 4(5. 
Winternitz: Habil.-Schrift. Halle, 1902. 

CUTANEOUS IRRITANTS OR COUNTERIRRITANTS 
Almost all volatile "lipoid-soluble" substances cause sensory irri- 
tation and rubefaction, for they readily penetrate through the skin 
and its fatty layer and into the sensory nerve-endings. 

Carbon dioxide in the carbonic acid baths, dilute alcohol (20-40 
per cent.), and chloroform (with an equal amount of olive oil) act 
in this fashion. 

Another widely used counterirritant is turpentine, which is ob- 
tained by the dry distillation of the resins of the different coniferge 
and which is an ingredient of many plasters, etc., used as cutaneous 
irritants. 

It is a mixture of pinene, C 10 H 16 , with small amounts of other terpenes and 
traces of organic acids. Rectified spirit of turpentine is obtained by distilling 
the crude product with lime. 

When left in contact with the skin for a time, it causes redness and 
burning of the skin, while on longer contact it penetrates more deeply 
and causes vesication and pustulation. It irritates the gastric and 
intestinal mucosae but slightly, so that 1.0 gm. or more may without 
injury be taken several times daily. It is readily absorbed and is 
excreted through the kidneys, in part unchanged and in part as 
terpene alcohol in conjugation with glycuronic acid, the urine acquir- 
ing some antiseptic power and an odor resembling that of violets. 

The terpenes and resinous acids of copaiba, cubebs, and sandal- 
wood oil also render the urine feebly antiseptic as well as astringent, 
for the resinous acids excreted in it precipitate albumin (Vieth). 
These actions account for the favorable effect of these drugs in 
inflammations and infections of the lower portion of the urinary 
tract. 

In order to avoid irritation of the stomach and intestines, it is best to 
employ for this purpose the salicylic ester of the oil of sandal-wood (santyl) or 
esters of terpene alcohols, which are non-volatile and very slightly irritant. 
These drugs, however, during their excretion can cause inflammation of the renal 
capillaries, just as they do in the skin, dilating them and rendering them more 
permeable, so that diuresis is augmented, and at times albuminuria and hema- 
turia may result from their administration. [Probably only when large doses 
are taken or when the kidney is already damaged are these drugs likely 
to cause any serious renal injury, but this action should be borne in mind when 
considering their use in large doses or in nephritic cases. — Te.] 

Oil of Juniper. — The essential oil of Juniperus sabina, a mixture of the 
alcohol, sabinol, and of various terpenes, is extremely irritant to and often 



COUNTERIRRITANTS 487 

causes necrosis of the kidney epithelium, as well as elsewhere. Taken internally 
it causes gastro-enteritis, hematuria, and marked kyperaemia of the pelvic organs, 
and even abortion. Externally it is employed as an ointment for the gradual 
removal of polypoid growths, etc. [It is present in gin. — Tk.] 

A small portion of the turpentine absorbed (also of cubebs, 
copaiba, and oil of sandal-wood) is excreted through the lungs, and 
may act as a disinfectant and deodorizer in purulent bronchitis or 
in gangrene of the lung. In addition turpentine, particularly when 
inhaled, diminishes the bronchial secretions, and may be consequently 
used with advantage in certain cases of bronchitis. 

Camphor, C 10 H 16 0, in alcoholic or oily solution, may be used as a 
mild counterirritant. 

Arnica, which is widely used by the laity, contains arnicine, a 
substance which causes cutaneous irritation. 

Acetic and formic acids in various dilutions may be used for 
similar purposes, as is 

Ammonia, which is an ingredient of various liniments, and which 
is also used in smelling salts as a means of reflexly stimulating the 
respiratory and vasomotor centres. 

When concentrated ammonia is respired, it immediately causes burning 
pain, a reflex spasmodic closure or oedema of the glottis, and violent irritation 
with swelling and exudation in the laryngeal and tracheal mucous membranes. 
Strong aqueous solutions, when left in contact with the skin, cause within 15 
minutes severe burning, redness, and vesication. 

Dilute alkalies, such as solutions of potash or soda or alkaline 
soaps, especially sapo mollis, in pure form or as the tincture, produce 
the same effects. Aqueous solutions of the alkaline carbonates or of 
soaps emulsify the cutaneous fats and facilitate their removal, and 
with prolonged action loosen the superficial layers of the skin and 
reach the sensory nerve-endings, causing burning or pain. 

The alkaline sulphides are more powerfully irritant, for they 
soften and dissolve the keratin of the epidermis and consequently 
readily penetrate it. Sulphur itself, when applied in salves or pastes, 
exerts similar but much weaker actions, for in contact with the skin 
it is gradually transformed into alkaline sulphides (p. 209). When 
a paste of calcium sulphide, prepared by the action of ILS on milk 
of lime, is rubbed on a hairy part, it acts as a powerful depilating 
agent, and is actually used in the Orient as a substitute for the razor. 

Substances insoluble in the lipoids, such as most of the indifferent 
sails, do not penetrate the skin in appreciable amounts unless they 
penetrate into the sebaceous glands,* where they may be absorbed 
by the living epithelial cells, or unless the skin has been rendered 
more permeable by prolonged warm baths or poultices. Previous re- 
moval of the cutaneous fat, by ether, alcohol, or chloroform, facilitates 
the absorption of such salts (Wintemite . 

* Surf] substances are consequently not absorbed when applied as ointments 

unless they are driven into the skin by prolonged and vigorous friction. 



488 PHARMACOLOGY OF INFLAMMATION 

Salt Baths and Sea Baths. — None of the constituents of such 
baths are directly absorbed by the skin, except in so far as a certain 
amount remains on the skin and, as a result of friction, is gradually 
driven into the glands and between the epithelium. During this pro- 
cess they cause a mild but often very lasting stimulation of the skin, 
with a resulting redness and feeling of warmth, effects which may 
reflexly produce a stimulation of the nervous system and metabolism. 

Iodine is a very efficient counterirritant and one especially adapted 
to cause sharply limited or readily modified counterirritation. For 
this purpose it is employed in the form of its tincture (7 per cent, 
in alcohol) or as Lugol's solution (5 per cent. I, 10 per cent. KI in 
water). 

As iodine is volatile at ordinary temperature, it does not long 
remain on the exposed surface of the skin, so that its deep brown 
stains quickly fade to a light yellow. Its local application is followed 
by' a feeling of warmth and prickling and by a hyperaemia of the 
skin. Prolonged or frequently repeated application may cause the 
development of large blisters. The hyperaemia and serous infiltration 
caused by it may extend quite deeply into the tissues and result in 
a cytolytic dissolution and absorption of diseased tissues or of patho- 
genic material. Iodine is consequently a favorite agent for the treat- 
ment of inflammatory tumors, swollen glands, arthritis, etc. Solutions 
of iodine may also be injected into cysts, hydroceles, etc., after they 
have been emptied, to cause inflammatory reactions leading to ob- 
literation of such cavities. If, however, too large amounts are thus 
injected, serous poisoning may result from the iodine which is ab- 
sorbed, and which is eliminated by the alimentary mucosa and by the 
kidneys, causing violent gastro-enteritis with persistent vomiting, 
serous exudates into the pleural cavity, nephritis, and profound coma 
(Rose). 

Solutions of iodine act much more powerfully on mucous mem- 
branes than on the skin, and cause destruction of the superficial 
layers and intense hyperaemia of their lower layers. As the sensory 
nerve-endings in the mucosa are benumbed or killed, the points of 
application remain for some time benumbed and almost insensitive. 

Oil of Mustard is also a member of this group of cutaneous 
irritants. 

It is formed by the action of a ferment on potassium myronate (sinigrin), 
C M H, c NS 2 KO D , which is contained in the seeds of Brassica nigra, and which is 
decomposed hydrolytically into the oil of mustard, isosulphocyanallyl, CSNC 3 H 5 , 
dextrose, and potassium bisulphate. This ferment, myrosin, is contained in the 
mustard seeds and becomes active when the pulverized seeds are moistened with 
water. [As this ferment is destroyed by heat, care should be taken when making 
poultices that the water be not too hot, otherwise the ferment is destroyed and 
as a consequence the mustard's activity is more or less completely destroyed. — 
Tb.] 

This oil has an extremely irritant odor, and when applied to the 
skin causes burning and redness, and, if sufficiently concentrated or 



VESICANTS AND SUPPURANTS 489 

if the action be prolonged, causes vesication. It is used as a cutaneous 
irritant either in the form of a mustard plaster or leaf, in which 
form its action develops gradually, producing a gradually increasing 
irritating effect, or as a liniment in the form of a tincture or spirit 
of mustard, in the strength of 2 parts to 100. 

Care should be taken not to permit it to cause more than pro- 
nounced redness of the skin, for experience has shown that the 
blisters caused by it heal very slowly. The simultaneous application 
of preparations containing ammonia has also to be avoided, for 
ammonia and mustard oil readily combine to form thiosinamine with 
the formula 

CS - NGHs + NH 3 = CS<^ 

Fibrolysin. — Thiosinamine, or allyl sulphocarbarnide, when combined with 
sodium salicylate is known as fibrolysin. When applied to the skin it produces 
no effects, but when injected subcutaneously — thiosinamine best in 15 per cent, 
alcoholic solution, fibrolysin best in an aqueous one — it causes severe pain and 
hypersemia, and after absorption causes, it is claimed, a thus far unexplained 
softening and absorption of the connective tissue of scars and other connective- 
tissue growths. It has consequently been recommended as a means of bringing 
about the softening of cicatricial contractures in the extremities and of strictures, 
— for example, strictures of the oesophagus. Teleky states that under its influence 
fresh adhesions, such as those following laparotomies, fistula operations, etc., 
readily loosen up, an effect which may be distinctly undesirable. 

BIBLIOGRAPHY 

Rose: Virchow's Arch., 1866, vol. 35. 

Teleky: Ztrbl. f. d. Gr. d. Med. u. Chir., 1901, vol. 4, literature. 

Vieth: Med. Klin., 1905, No. 50. 

Winternitz: Arch. f. exp. Path. u. Pharm., 1891, vol. 28. 

VESICANTS AND SUPPURANTS 

Of the various substances which may cause vesication, only three 
are actually used in medicine, the Spanish fly or cantharis, Daphne 
mezereum, and the fruit of Anacardium occidentale. 

Cantharides. — Although their common name is Spanish flies, these 
are neither Spanish nor are they flies, but beetles, from 2 to 3 cm. 
long, of an emerald-green color, which are distributed throughout 
both hemispheres in the tropical and temperate zones. Their bodies 
contain an acid lactone, cantharidin, which is insoluble in water, 
but readily soluble in fats, ether, and alcohol, and to which they owe 
their activity. A number of other allied species also contain can- 
tharidin. 

Cantharidin is applied to the skin in the form of a plaster, oint- 
ment, or collodion, either to cause a local reddening or hyperemia 
or to cause vesication. Its application is quite quickly followed by 
a reddening of the skin and pain, and after some hours the epidermis 
is raised from the coriutn and a blister containing serum and many 
leucocytes is formed, by which time the pain and the redness have 



490 PHARMACOLOGY OF INFLAMMATION 

disappeared and the corium has become pale. When the blister is 
emptied, the epidermis reforms rapidly, as a rule, and the blister 
heals promptly, but, if cantharidin be again applied to the exposed 
corium, violent purulent inflammation may result. 

AY hen swallowed in small amounts, such as 0.5 c.c. of the tincture, 
it causes only a feeling of warmth in the epigastrium ; but large doses 
may cause violent gastro-enteritis, swelling of the submaxillary 
glands, and active salivary secretion and nephritis. When very small 
doses are repeatedly administered or when small quantities of can- 
tharidin are repeatedly applied to the skin, as a result of the absorp- 
tion of the cantharidin a severe glomerulonephritis, and, under some 
conditions, a violent irritation of the urogenital tract, with frequent 
painful micturition and hyperemia and sensory irritation of the 
genital organs, may occur. These last effects account for the formerly 
not infrequent abuse of cantharides as an abortificient and as an 
aphrodisiac. 

The kidney lesions appear to be dependent on the reaction of the urine, 
for. according to Ellingcr, cantharidin causes only a slight albuminuria in rabbits 
as long as the urine is alkaline, but, if this becomes acid, causes a very violent 
hemorrhagic nephritis, which may prove fatal. Consequently, with threatened 
cantharidin poisoning in man the administration of alkalies would appear 
to be indicated. 

Cantharidin, being a lactone, combines in the presence of water with alka- 
lies, forming soluble salts. Sodium cantharidinate has been employed, on Lieb- 
rcich's recommendation, in the presence of already existent inflammation, to 
increase the permeability of the smaller blood-vessels, with the idea of causing 
more pronounced serous infiltration with its often curative effects. When thus 
employed, it is administered subcutaneously in very dilute solution (1: 10,000), 
and, while curative effects have been obtained by its use in such conditions as 
lupus, such administration has often caused renal irritation, so that its use has 
been abandoned. 

The dried bark of Daphne mezereum has been employed as a 
household, remedy as a vesicant and suppurant. Cardol, a very irri- 
tant oil obtained from husks of Anacardium occidentale (cashew- 
nut), was also formerly employed as a vesicant. 

Almost all of the other vesicants and suppurants mentioned in the 
introduction do not penetrate the intact epidermis, but produce their 
harmful effects on the vessels only when applied to open wounds or to 
mucous membranes, or when absorbed from subcutaneous tissues or 
from the alimentary canal. 

Abrin and tuberculin are the only ones of them which are at 
present of practical importance. The former is a toxic substance, 
probably of proteid nature, contained in the seeds of Abrus praeca- 
torius, which w T hen applied to mucous membranes causes a more or 
less violent purulent inflammation, and which is at times employed 
in ophthalmological practice (see p. 160). Concerning tuberculin 
the reader is referred to page 545. 

BIBLIOGRAPHY 

Ellinger: Miinchn. med. Woch., 1905, No. 8. 
Liebreich: Therap. Monatsh., vol. 5, p. 169. 



ESCHAROTICS OR CAUSTICS 491 

ESCHAROTICS OR CAUSTICS 

These are used not to cause a healing inflammation, hut to destroy 
pathological tissues. Such destruction is produced instantaneously 
by the action of such powerful chemical substances as the caustic 
alkalies, concentrated acids, and certain of the salts of the heavy 
metals. 

The caustic alkalies, fused caustic potash, etc., dissolve proteid 
and keratin, with the formation of a viscid water-soluble mass, 
through which the caustic penetrates further, so that its painful 
caustic action is not sharply limited. By the addition of the less 
soluble lime, it is possible to limit somewhat the depth and extent 
of this caustic action. 

Acids. — Lactic acid also dissolves proteid and keratin, and con- 
sequently its caustic action is not sharply limited and is rather 
persistingly painful. However, as healthy cells are relatively resist- 
ant to it, it may be employed to electively destroy pathological 
tissues. 

Of the other acids, fuming nitric acid and trichloracetic acid are 
the ones most used as caustics, as both of these form from the de- 
stroyed tissues a firm leathery eschar. It is possible to produce with 
them a cauterization which is sharply limited and accompanied by 
pain of but short duration. The eschar caused by nitric acid has a 
lemon-yellow color, due to the nitrified proteid (xanthoprotein) ; 
that produced by concentrated aqueous solutions of trichloracetic 
acid is white. 

Chromic acid, Cr0 3 , which occurs as red crystals readily soluble 
in water, is a very powerful caustic, formerly much used, but now 
abandoned because too poisonous. 

Metallic Salts. — Those salts of the heavy metals which are hydro- 
lytically dissociable act as caustics in the same fashion as, although 
more weakly than, the free acids, precipitating proteid, with the 
formation of- acid albuminates and metal albuminates, and thus de- 
stroying all protoplasm. They are employed either in pure form as 
caustic pencils, in concentrated watery solution, or in the form of 
pastes. 

If all the constituents of the protoplasm are not equally affected 
chemically by a substance, but if only certain of them are thus acted 
upon, the cell is not necessarily destroyed, but only damaged and, 
in certain cases, gradually killed. Thus, for example, the mere dis- 
turbance of the osmotic condition of a cell may bring about its death 
and decomposition, particularly if its vitality is already depressed. 
In such fashion pure water, by diminishing the osmotic tension of 
the superficial cells of the gastric mucosa, may kill them and thus 
favor the regeneration of new cells, while concentrated salt solutions, 
pure glycerin, etc., may produce similar result by augmenting their 
osmotic tension. 



492 PHARMACOLOGY OF INFLAMMATION 

Arsenic, in the form of arsenic trioxide, a white tasteless powder, 
soluble with difficulty in water, is a most certain means of bringing 
about the gradual death of cells. When applied to wounds or mucous 
membranes, it does not directly cause a sensory or inflammatory irrita- 
tion, but those cells which have come in contact with arsenic in 
solution gradually die and after some days undergo necrotic decom- 
position. Iu this fashion it may cause destruction of tissues to a con- 
siderable depth. It is employed with good results in dentistry as a 
means of killing and destroying the nerves in decayed teeth and 
their roots. 

Antimony oxide also causes cell necrosis in quite the same fashion. 
The most important antimonial compound is tartar emetic, in which, 
however, the antimony does not exist as a free ion Sb"', but as the 
ion SbO' which apparently has no direct toxic actions. This salt is 
decomposed by acids, with the formation of the acid Sb(OH 3 ), or the 
oxide Sb 2 3 , both of which are directly active. Consequently, salves 
or pastes containing tartar emetic, when applied to the skin, cause 
necrosis only in those places where it is decomposed by an acid 
secretion and changed into an active form, — i.e., only in the mouths 
and the follicles of the cutaneous glands, in which small areas of 
necrosis are produced, forming pustules resembling those of variola. 

Enzymes. — Certain digestive enzymes, such as trypsin and papain, 
a proteolytic ferment obtained from Carica papaya, have also been 
used to bring about a gradual destruction of pathological tissues. 

THE INHIBITION OF INFLAMMATION 
Inasmuch as inflammation is reflexly excited, or at least markedly 
augmented, by sensory stimuli, it follows that inflammation will be 
more or less inhibited by all agents which diminish or prevent sensory 
stimulation at the seat of inflammation. Further, all agents which 
prevent the abnormal dilatation and permeability of the vessels, and 
all which diminish the motility of the leucocytes, will also tend to 
prevent or lessen inflammatory reactions; and, lastly, inflammatory 
processes may be etiotropically combated by removing or rendering 
harmless the pathogenic agents causing the inflammation. 

In accordance with the above, antiphlogistic agents, or agents re- 
straining inflammation, may be grouped under the three heads of 
analgesic, astringent, and etiotropic agents. The last of these will 
be discussed in another chapter. 

1. ANALGESIC ANTIPHLOGISTIC AGENTS 

One of the most frequently used of these is cold, obtained by the 

local application of ice-bladders, etc. It goes without saying that the 

effect of cold in slowing the circulation, paralyzing the leucocytes, 

and constricting the vessels aids in controlling the inflammation. 

Spiess in particular has called attention to the use of analgesics in 



INHIBITION OF INFLAMMATION 493 

controlling inflammation. As emphasized by Bruce, agents used for 
this purpose should produce a somewhat lasting local analgesic effect, 
and should consequently be such as will not be dissolved and ab- 
sorbed rapidly, for otherwise they would leave the place of applica- 
tion too quickly. Consequently, only rather insoluble ones, such as 
anassthesin (p. 134), are adapted for this purpose, or they must 
be applied in large amounts in case they are sufficiently nontoxic. 
An example of the latter type would be alcohol, with which a dressing 
for a paronychia is saturated. In the case of the much-used chemically 
indifferent protective agents, such as gum arabic, starch paste, in- 
different salves, plasters, and dusting powders, the favorable effects 
on the inflammation are undoubtedly chiefly due to their power of 
shielding the parts from chemical or mechanical sensory irritation. 

BIBLIOGRAPHY 
Bruce: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 424. 
Spiess: Miinchn. med. Woch., 1906. 

2. ASTRINGENTS 

As has already been stated (pp. 212, 213), astringents form a 
more or less firm and impenetrable coating on the surfaces of wounds 
of mucous membranes by coagulating the superficial layers of cells, 
so that the glands and lymph-spaces are partially blocked, while the 
gland-cells themselves are altered and their secretions checked 
(Schiitz) so that the parts become dry. They also become pale and 
constricted, because the smaller vessels are constricted and their 
walls rendered less permeable, and, consequently, the serous infiltra- 
tion of the tissues and the emigration of the blood-cells is lessened 
or entirely prevented (Heinz). 

Moreover, it must not be forgotten that the astringents also exert 
some etiotropic actions, as they act on the exciters of inflammation, 
killing pathogenic microbes, and, what is probably even more im- 
portant, precipitating or destroying the inflammatory cytolytic fer- 
ments and those substances which are formed during every cell 
necrosis and which have the power of exciting inflammation. With 
the removal of these phlogogenetic substances, the irritation of the 
sensory nerve-endings and the pain both decrease, so that in this 
fashion the astringent may also relieve pain. In this particular the 
astringents show a certain resemblance to the etiotropic antiseptics, 
which will be discussed in a later chapter. 

The chief members of this group are the various tannins, some of 
the salts of the heavy metals and of aluminum, and calcium hydrox- 
ide. 

It is hardly necessary to state that numerous organic Bilbatances, such as 
picric acid, which precipitate and harden proteid, produce an astringent effect, 

but, on account of other properties, such as toxicity, volatility, etc., are practically 
ill adapted for such employment. Among tbem mention may hereby !><■ made of 
formaldehyde, which may be used in dilute solution (1 to 10 per cent.) to 
harden the skin and to prevent localized excessive sweating. 



494 PHARMACOLOGY OF INFLAMMATION 

In a former chapter sufficient has already been said about the 
various tannins (page 214 ff.), and in the same place bismuth sub- 
nitrate and subgallate, the subacetate and acetate of lead, silver 
nitrate, and lime water have all been discussed. 

All the caustics mentioned above, which form a firm and tough 
eschar, when used in high dilution act as astringents, so that, even in 
the case of a cauterization, such as that produced by silver nitrate, 
the traces of the caustic agent which penetrate into the underlying 
tissues act there as astringents. Consequently the curative effects of 
many of these substances depend on such a combination of their 
caustic and astringent actions. 

Of such caustics the most important practically are silver nitrate, 
the sulphates and acetates of copper, alum and zinc, and the 
liquor ferri sesquichlorati. The latter is also employed as a means of 
checking bleeding, on account of its power of causing coagulation of 
the blood. 

If such caustics do not form solid compounds with the tissues, 
but, like the salts of mercury, arsenic, and antimony, form only soft 
or water-soluble products, they produce no astringent effects what- 
ever. On the other hand, the caustic action is very slight or entirely 
absent in the case of those substances which, on account of their slight 
solubility in water or their slight power of diffusion, are able to pro- 
duce only a weak and extremely superficial chemical reaction. In 
addition to the tannins, the following are examples of such substances : 
Zinc oxide, lead oxide, lead carbonate, lead subacetate, and the 
subnitrate, subgallate, and subsalicylate of bismuth. 

BIBLIOGRAPHY 

Heinz: Virchow's Arch., 1889, vol. 116. 

Schiitz: Arch. f. exp. Path. u. Pharm., 1890, vol. 27. 

Bismuth Salts. — While the subgallate and subsalicylate of bis- 
muth possess the advantage over the subnitrate that, when admin- 
istered internally, they cannct cause nitrite poisoning,* they are 
inferior to it in that neither gallic nor salicylic acids are astringents. 

Although the basic bismuth salts are insoluble in water, and can- 
not be absorbed in appreciable amounts either by mucous membranes 
(even inflamed ones) or by granulating wound surfaces, still, when 
brought in contact with fresh wounds, they without exception are 
transformed into soluble compounds of unknown character, which 
are absorbed, and consequently under these conditions they may 
cause serious 

Bismuth Poisoning. — This very closely resembles subacute 
mercurial poisoning, and is characterized by the formation of dirty, 
dark-colored ulcerations in the mouth, particularly where the tongue 
or the gums are eroded, and by extensive necrosis in the large in- 

* See p. 216. 



INHIBITION OF INFLAMMATION 495 

testine, and also by glomerulonephritis (Eocher, Mahne). The ulcer- 
ations in the mouth and the large intestine result from the intra- 
cellular and intravascular precipitation of the oxide of bismuth by 
hydrogen sulphide (H. Meyer u. Steinfeld). 

All other bismuth compounds, such as xeroform (bismuth tribro- 
mophenol), orphol (bismuth /3-naphthol), airol (bismuth iodosubgal- 
late), etc., may produce toxic effects, and it is consequently entirely 
incorrect to state, as is too often done, that any bismuth compound 
is absolutely non-toxic. 

BIBLIOGRAPHY 

Kocher: Volkmann's Klin. Vortr., 1882, p. 224. 

Mahne: Berl. klin. Woch., 1905, No. 42. 

Meyer, H., u. Steinfeld: Arch. f. exp. Path. u. Pharm., 1885, vol. 20. 

Aluminum Salts. — The above is also true for the salts of alumi- 
num, for they too are toxic if absorbed (Stem). Aluminum subacetate 
and dilute solutions of alum, aluminum sulphate, alsol (A. aceto- 
tartrate), and aluminol (A. naphtholsulphonate) are all used as 
astringents. 

BIBLIOGRAPHY 
Siem: Diss., Dorpat, 1886. 

Lime Salts. — In a former section (p. 217) the manner in which 
lime water acts as a local astringent has been explained, and also its 
superiority, for certain cases, to all other acid-reacting or insoluble 
astringents, owing to its power of dissolving mucus. This property 
is of particular value in the treatment of diphtheritic inflammation 
of the throat, in which thick pseudo-membranes containing much 
mucin are formed (Harnack) . 

The neutral-reacting calcium chloride, however, may also in a 
certain sense be considered an astringent, and a remotely acting one 
at that. In animals, in which the total amount of calcium has been 
increased by the subcutaneous injection of calcium chloride, inflam- 
mation does not occur at all or only in a mitigated form. 

In sucti animals the instillation of oil of mustard or of abrin into the con- 
junctiva is not followed by the usual pronounced hyperemia, chemosis, and pus 
formation, and pleural and pericardial effusions also fail to result from certain 
injections and poisonings which ordinarily cause them (Chiari) , while the 
development of exanthemata is prevented or at least rendered very difficult 
(Wright, Luithlen). It appears, therefore, that calcium acts on the smaller 
blood-vessels, and perhaps also the lymph-vessels, so as to render them less per- 
meable to the blood plasma and cells. 

These effects are produced most certainly by subcutaneous injection 
and last about 21 hours, but they may also follow oral administra- 
tion, although more slowly and in slighter degrees. In man 100 c.c. 
of a 2 per cent, solution of chloride of calcium may be taken internally 
(Leo), but only dilute solutions (1-2 per cent.) should be administered 
subcutaneously, as more concentrated ones cause necrosis at the point 
of injection. It must also be emphasized that calcium salts are by no 



496 PHARMACOLOGY OF INFLAMMATION 

means non-toxic, for animals, into which 0.3 to 0.4 gm. CaCl 2 per 
kilo have been injected subcutaneously, die in a few days as a result 
of a central paralysis. 

BIBLIOGRAPHY 

Chiari u. Janusehke: Arch. f. exp. Path. u. Pliarm., 1911, vol. 65, p. 120. 

Harnack: Berl. klin. Woch., 1888, No. 18. 

Leo: Deut. med. Woch., 1911, No. 1, here literature. 

Luithlen: Wien. klin. Woch., 1011, No. 20. 

Wright, A. F.: Lancet, 189G, vol. 1, p. 153; 1905, vol. 2, p. 1096. 

Epinephrin acts in a different fashion, but also prevents inflam- 
mation. As is well known, when subcutaneously or intravenously ad- 
ministered, it markedly delays the absorption of chemical substances 
from serous cavities and from the subcutaneous tissues, probably on 
account of the persistent contraction of the blood and lymph 
capillaries (Meltzer, Exner). 

As shown by recent experiments of Frohlich, this vasoconstriction also pre- 
vents inflammatory transudation, for, after the intravenous injection of the 
more persistently acting and less toxic d- epinephrin, the oil of mustard does not 
cause inflammation of the rabbit's conjunctiva. 

BIBLIOGRAPHY 

Exner, A.: Ztschr. f. Heilk., 1903, No. 12. 

FrShlich: ZbL f. Physiol., 1911, vol. 25, No 1. 

Meltzer u. Auer: Proc. Soc. exp. Biol, and Med., 1903-04, vol. 1, p. 38. 

Quinine may also in a certain limited sense be considered a sub- 
stance possessing the power of inhibiting inflammation, for it dimin- 
ishes the motility of leucocytes and thus prevents their diapedesis, 
as proven by the observations made by Binz on the inflamed mesentery 
of the frog. It is consequently not impossible that threatening forma- 
tion of pus may be prevented by the internal administration of 
quinine, or that purulent foci already extant may be prevented from 
spreading (Binz).'* In purulent catarrhal inflammations of the upper 
air-passages, large doses of quinine, according to common experience, 
exert an inhibitory influence on the inflammation. This may justify 
the presence of quinine as a constituent of various coryza tablets, f 

According to Winternitz, ethereal oils also, after their absorption 
into the blood, have the power of limiting the formation of exudates 
in inflamed tissues and of favoring their absorption. 

BIBLIOGRAPHY 
Binz: Virchow's Arch., vol. 46. 
Winternitz: Arch. f. exp. Path. u. Pharm., 1901, vol. 46. 

* Satisfactory experimental and clinical proof of such action is, as far as the 
translator knows, still lacking. 

t [Inasmuch as these tablets contain only small amounts of quinine it is 
probable that such effects as they produce are due entirely to the atropine which 
almost all of them contain. — Tk.] 



CHAPTER XVII 
ETIOTROPIC PHARMACOLOGICAL AGENTS 

In so far as drugs alter the functions of the various organs in the 
body they may be looked upon as acting organotropically. In con- 
trast to these is a group of drugs with which we are able to influence 
the causative agents of disease without producing essential changes 
in the functions of the various organs, and which may consequently 
be called etiotropic drugs. The causes of disease against which they 
direct their activity may be animate or inanimate, — i.e., parasites, 
bacteria, protozoa, etc., or poisons, such as the so-called toxins. 

Outside of the body the destruction of bacteria is attained by the 
use of disinfectant drugs and various physical agents, particularly 
heat. On the surface of wounds, mucous membranes, etc., bacteria 
may be combated by antiseptics, while against the animal parasites 
of the alimentary canal the antiparasitics are used. In such eases 
etiotropic drugs come in contact with the pathogenic organisms not 
inside of the tissues but on the surface of the higher organism, while 
in other cases it is possible to destroy the disease-producing organisms 
(protozoa) in the tissues themselves without essentially disturbing 
the organic functions of the body of the host. This we call specific 
antiseptic therapy. 

If poisons taken into the stomach are rendered harmless by the 
proper antidotes, — for example, phosphorus by copper sulphate, 
arsenic by calcined magnesia, — the antidote really acts on the cause 
of disease in a fashion analogous to the manner in which an an- 
thelmintic acts on a parasite. In a similar fashion inanimate causes 
of disease, even after penetration into the tissues, may be directly 
attacked by antidotal agents. Thus, hydrocyanic acid and various 
cyanide compounds may be transformed into non-toxic substances by 
sodium hyposulphite, even after they have been absorbed into the cir- 
culation. As these antidotes have already been discussed elsewhere, 
they will not be considered in this section, but, of the inanimate causes 
of disease, only the toxins, which stand in the very closest relation- 
ship to living pathogenic agents, will be dealt with in connection with 
antitoxin therapy. 

GENERAL ANTISEPTICS 

Tn high dilutions antiseptics do not kill bacteria but only inhibit 
their growth and multiplication, while in somewhat greater concen- 
tration they kill the adult forms but not the spores, these being de- 
stroyed only by strong solutions of the most powerful antiseptics. 

Methods ov Investigatm)!?. — Tn order <«> determine the power of a Bubstance 

to inhibit bacterial development, — i.e., its antiseptic power, — it is added to the 
32 497 



498 ETIOTROPIC PHARMACOLOGICAL AGENTS 

fluid culture-medium in varying amounts, and the lowest concentration is deter- 
mined which prevents the growth of the bacteria or the development of the 
spores. In investigating the disinfectant value — that is to say, the bactericidal 
power — of a substance, silk threads, pieces of glass, beads, and the like are cov- 
ered with bacteria or spores, in so far as it is possible in equal numbers, and these 
test objects are left for different periods of time in the disinfectant solution, 
which is kept at a fixed temperature. After the disinfectant has acted upon 
these objects, the bacteria must be, as far as possible, freed from it, in order 
that a portion of the disinfectant may not be carried over into the fresh culture- 
medium, for, as even very small amounts of disinfectants are sufficient to inhibit 
bacterial growth, this might lead to the false conclusion that the bacteria had 
been killed. Thus, for example, following a suggestion of Geppert, who was the 
first to call attention to this source of error, mercurial compounds are rendered 
harmless by precipitating them with ammonium sulphide. For further details 
concerning the method of determining disinfecting powers the reader is referred 
to text-books on bacteriology. 

As in all living cells, in the bacterial cell also the carrier of vital 
functions is a mixture of colloids in a state of "Quellung" or hydra- 
tion, principally proteids and' lipoids, which latter are for the most 
part substances of as yet unknown constitution but which resemble the 
fats in their solubilities. In this mixture of a' certain definite structure, 
the protoplasm, the ferment actions and the vital functions of the 
cells, such as assimilation, growth, and reproduction, take place in an 
aqueous solution of salts, the concentration of which is definite for 
each organism but varying within certain limits with the varying 
species of bacteria. A change of the salt content of the medium may 
inhibit the vital activity of the bacteria, and may, with them as with 
other plant cells, cause plasmolysis (.1. Fischer), while drying renders 
the life of the bacteria latent, but destroys it only after very complete 
removal of all water or when the drying has lasted for a very long 
time. 

Every alteration in the chemical composition of the protoplasm causes an 
injury to the bacterial cells. An example of the delicacy with which these cells 
react to alterations in the chemical composition of the medium in which they 
are placed, is furnished by the anaerobic micro-organisms, whose life is so depend- 
ent on a very low oxygen tension that an increase in the amount of oxygen in 
the surrounding medium is fatal or harmful to them. 

Most especially an alteration or change affecting the colloids or 
lipoids results in damage to the protoplasm, and consequently every 
foreign substance must act as a poison to bacteria if it is able to pene- 
trate into their interior and enter into a chemical or physicochemical 
reaction with their vitally important constituents. Inasmuch as these 
constituents of the protoplasm of all animal and vegetable cells are 
similar, and as the bacterial cells in respect to their permeability do 
not differ essentially from other cells, it follows that all general 
cytotoxins are also general poisons for bacteria. 

While in all its detail it is not known on which of these reactions the 
bactericidal power of the general antiseptics depends, the disinfect- 
ing power of the salts of the heavy metals, of acids, and strong alka- 
lies is attributed to their power of producing changes in the proteid 



GENERAL ANTISEPTICS 499 

constituents of the bacteria, for tlieir bactericidal power runs 
parallel with their power of reacting with proteids. In connection 
with the absorption of poisonous substances which possess affinities 
for the lipoids, their toxic action may be attributed to a disturbance 
of the relationship between the lipoids and the other constituents of 
the bacterial cells. Similarly the alteration of the protoplasm by 
powerful oxidizing agents, which also act as antiseptics, is readily 
understood. On the other hand, however, prussic acid poisons the 
cells by inhibiting oxidation, probably by inhibiting the oxidases. It 
is thus seen that the bacterial cells may be affected in many quite 
different fashions. 

Inasmuch as the disinfectants are also general cell poisons, the 
most that may be expected is quantitative differences between the 
susceptibility of the bacteria and that of animal cells. These may 
in the first place rest upon differences in permeability. 

The outer layer of the protoplasm, or the plasma skin, which in 
vegetable cells lies on the inner side of the cell membrane, behaves 
in many bacteria in a manner not essentially different from its be- 
havior in other animal and vegetable cells, being readily permeated 
by water and by many substances which are soluble in lipoids but 
permeated with difficulty by salts. Such bacterial cells consequently 
readily undergo plasmolysis. In other varieties, however, this outer 
layer is readily permeable for salts also. Consequently the proto- 
plasm of bacteria is, generally speaking, no- better protected from an 
elective absorption by its outer layer than is the case with other cells. 

The behavior of the external cell membrane is of more importance. In other 
vegetable cells this cellulose covering is readily permeable for all substances, and 
consequently, under the influence of substances with little power of permeation, 
the differences in osmotic pressure, which lead to plasmolysis, occur only on both 
sides of the external layer of the protoplasm. The bacterial cell membrane, how- 
ever, does not consist, as in other vegetable cells, of pure cellulose but also 
contains nitrogen, and consequently its permeability is not to be taken for granted 
as being the same as that of other vegetable cells. On the contrary, it forms a 
barrier which opposes a resistance to the entrance into the cell of various sub- 
stances. This may be observed in connection with the action of poisons which 
after passing through the cellulose membrane produce alterations in the con- 
stituents of the plasma skin. Thus, for example, other vegetable cells are so 
rapidly killed by % normal (molecular) XaCl solution which is saturated with 
iodine that plasmolysis does not occur, for the iodine enters immediately into a 
chemical reaction with the surface layer of the protoplasm and abolishes its 
Bemipermeability for the sodium chloride. On the other hand, one may produce 
plasmolysis of bacteria with this very same solution (A, Fischer), for in them 
the iodine penetrates nunc slowly through the external membrane of the bacteria. 
Solutions of various metallic salts behave in a similar fashion. 

The membranes surrounding the spores protect the internal con- 
tents of the cell much more effectively than does the external mem- 
brane of the bacteria, and it has been found that neither concentrated 
sodium chloride solution nor distilled water nor concentrated alcohol 
inflicts any damage iiporj spores, and thai water, even after months, 
penetrates into them with great difficulty. It is probable, therefore, 



500 ETIOTROPIC PHARMACOLOGICAL AGENTS 

that the astonishing resistance of spores to the actions of certain 
antiseptics is to be attributed to their slight permeability. Thus, for 
example, spores in general are particularly resistant to the toxic 
action of phenol and other lipoid soluble disinfectants which readily 
penetrate into the interior of adult bacteria. For instance, anthrax 
spores are killed by 4 per cent, carbolic acid only when exposed to 
it for days, while the adult bacilli are killed in 2-10 minutes by a 1 per 
cent, solution. Spores are also far more resistant to corrosive subli- 
mate, 0.1 per cent. HgCL killing anthrax bacilli in 10 minutes but the 
spores onty after two hours. This tough skin of the spores may con- 
sequently be considered as a protective organ comparable to the 
shells which cover most vegetable seeds. 

In addition to differences in the permeability of bacterial cells, 
differences in their susceptibility to various antiseptics is due in 
part to their varying power of retaining and storing up the 
penetrating substances in their protoplasm. When foreign sub- 
stances pass through the outer membrane, as a general thing they 
continue to diffuse throughout the protoplasm until an equilibrium 
has been established on both sides of the outer layer, but, if the 
foreign substance undergoes a chemical change after absorption into 
the interior of the cell, such an equilibrium cannot be established. 
Under such conditions bacterial cells may absorb considerable amounts 
of substances, even from very dilute solutions, and hold them fast 
in the form of new compounds. Thus, marine .alga? store up iodine in 
a form which is non-toxic to them, and certain plants are similarly 
able to absorb from soil containing considerable quantities of zinc 
as much as 13 per cent, of their weight in zinc salts (Czapek). In 
other cases, however, the new compound may be poisonous for the 
cell, so that a gradual poisoning results from its accumulation. The 
best-known example of such phenomena is the oligodynamic action 
of solutions of metallic salts first observed by N'dgeli in algae. 

In Bokorny's experiments, only water distilled from glass into glass was 
non-toxic for the alga\ while if the water had come into contact with copper, 
silver, lead, etc., it was found to be toxic to these organisms, although it was 
impossible by chemical reagents to recognize the presence of metallic compounds 
in this water, so great was the dilution. That the toxic action under these 
■conditions was due to a gradual accumulation of the metal in the cells of the 
algae, resulting from the absorption of the metal from the infinitely dilute solu- 
tion, is evidenced by the fact that by first bringing large quantities of algae 
into these solutions they could be rendered non-toxic for others introduced later. 

Lipoid Solubility of Antiseptics of Decisive Importance. — The 
solubility of the antiseptics in the outer layer of the protoplasm is 
the chief deciding factor for the rapidity with which they penetrate 
into the body of the bacteria. The power possessed by this membrane 
of dissolving many substances closely resembles the same power of 
fats, and, consequently, in general all substances which dissolve 
readily in fats are passively absorbed into the interior of these cells. 



GENERAL ANTISEPTICS 501 

When foreign substances penetrate into the cells from the tissue 
fluids of the body, — that is to say, from an aqueous medium, — their 
absorption will depend on the partition coefficient resulting from 
their solubility on the one side in water and on the other side in fat- 
like solvents. In accordance with this law, first promulgated by 
Overton, lipoid soluble substances must necessarily be readily and 
rapidly absorbed by bacteria. This fact gives to a group of organic 
antiseptics, the phenols, cresols, alcohol, etc., certain advantages over 
the inorganic ones, of which only a few, such as corrosive sublimate, 
iodine, and osmic acid, are soluble in lipoids. 

On the other hand, most of the salts, as well as the alkalies and 
inorganic acids, in short most solutions of strong electrolytes, are 
hardly at all soluble in fats, and consequently they are not absorbed 
through the unaltered plasma membrane. It is only when, by virtue 
of their power of precipitating or dissolving proteid, they destroy 
the external layers of the bacteria, that they are able to penetrate 
into the interior of these cells. 

From these points of view a division of the general antiseptics 
into two groups may be made, — those which are soluble in the lipoids 
and which consequently are absorbed into the superficial layers of the 
bacteria, which contain more or less lipoids, forming one group, 
while the second group consists of those which are insoluble in the 
lipoids but which, by attacking the proteid constituents of the 
bacterial cells, are able to penetrate into them. Such disinfectants 
as are soluble in the lipoids and at the same time precipitate pro- 
teids belong to both groups. 

The different manner in which the absorption of antiseptics of 
these two groups occurs is of more or less practical importance. The 
disinfecting power of the lipoid soluble antiseptics is determined 
largely by their partition coefficient between the cells and the sur- 
rounding media, and this is the reason why, when applied in oily 
solution, carbolic acid has no disinfecting power (Koch), for, on 
account of its great solubility in oil, it is held fast therein and does 
not penetrate into the bacterial cells. Further, carbolic acid pene- 
trates the bacteria with more difficulty from media containing much 
proteid than it does from pure water, for here its chemical affinity 
to proteid more or less neutralizes its tendency to enter into solution 
with flic lipoids of tin' bacterial bodies. 

The disinfectants of the second group form compounds with the 
proteids, which are more stable than the loose physicochemical com- 
binations formed by carbolic, acid and proteid, and consequently the 
disinfecting power of metallic sails is even more impaired by a 
medium containing much proteid than is the case with phenol. 

[NPLUBNCB OF Dissoci auii.itv. — That the reactions of the salts of 
the heavy metals, the acids, and the alkalies with the proteids of the 

bacteria are ion reactions is evidenced l>v the fact that the disinfec- 



502 ETIOTROPIC PHARMACOLOGICAL AGENTS 

tant power of such metallic salts as those of mercury is not dependent 
solely, as was formerly believed, on the amount of soluble mercury 
contained in their solutions, but runs parallel with the degree of dis- 
sociation of these solutions, — i.e., is determined by the concentration 
of the free mercury ions. If the total concentration of mercury were 
the decisive factor, it would necessarily follow that equimolecular 
solutions of different mercuric salts would exert equally powerful 
disinfectant actions, but, as a matter of fact, a comparison in the 
toxicity of mercury salts, which are dissociable in different degrees, 
clearly evidences the relationship between their toxicity and their 
dissociation (Paul u. Kronig, Spiro u. Scheurlen) . Thus, according 
to Hbber, the degree of dissociation and the disinfectant power of 
the three mercuric salts, the chloride, the bromide, and the cyanide, 
decrease in the same order (see table). The same thing may be 
shown for the behavior of other metallic salts, — for example, for the 
salts of silver and gold. 

Disinfecting Action on Anthrax Spores 

Number of colonies developing — 
Concentration of solution. After 20 min. After 85 min. 

HgCL 1 Mol. : 04 1 7 

HgBr, 1 Mol.: 64/ 34 

HgCy 2 1 Mol. : 16 Z c*> 33 

There is, however, a remarkable exception from this parallelism 
between disinfecting power and dissociability of solutions of the salts 
of mercury, for a comparison of the disinfecting power and dissocia- 
bility of solutions of mercuric chloride with those of mercuric nitrate, 
sulphate, and acetate, solutions of which are much more highly dis- 
sociated, shows that the mercuric chloride is much the strongest dis- 
infectant. 

Disinfecting Action on Anthrax Spores 

Number of colonies developing — 
Concentration of solution. After 6 min. After 30 min. 

1 Mol.: 10 I HgCL, 43 

1 Mol.: 1GI Hg(XO,) s +HNO, 2000 560 

1 Mol. : 16 Z HgS0 4 + 4H..S0 4 1800 592 

1 Mol. : 10 I Hg ( C 2 H 3 2 ) + C 2 H 4 O a 2737 1294 

This exceptional behavior of corrosive sublimate is to be attributed 
to its solubility in lipoids, a property not possessed by those other 
more highly dissociated salts. As a result of this property, mercuric 
chloride penetrates into the bacteria more rapidly than other salts, 
and consequently its disinfectant action occurs more promptly. How- 
ever, in ease of a more protracted action, such as is of importance 
in connection with inhibition by dilute solutions of the development 
of spores, the differences in the disinfecting or (more correctly 
speaking) the antiseptic power of the different salts disappear. 

The toxicity for tissue cells of the less highly dissociated quicksilver com- 
pounds is also relatively slighter, and consequently certain complex compounds 
of the metallic salts act much more mildly in the body. Dreser has shown that 



GENERAL ANTISEPTICS 503 

solutions of the double salt, potassium and mercury thiosulphate, require a much 
longer time for the development of their toxic actions on yeast-cells, frogs, and 
fish than do solutions of other salts of mercury, which contain the same total 
quantity of mercury in a more highly ionizable form. Potassium and mercury 
thiosulphate is a complex salt which may be looked upon as being the potassium 
salt of a mercuric-sulphurous acid, which in aqueous solution is dissociated into 
potassium ions and Hg(S 2 3 ) 2 ions. It is only as a result of the so-called second- 
ary dissociation of the complex mercurial ions that simple mercury ions are set 
free. Thus is explained the lack of toxicity of this double salt for cold-blooded 
animals, although for warm-blooded animals it is almost as toxic as the ionizable 
mercury compounds, for in the body of the warm-blooded animal the compound 
ion is rapidly decomposed and simple mercury ions are set free. In the same 
way other organic metal compounds lack both the chemical reactions of the metal 
ions and their physiological actions, if the metal is dissociated not as a free 
metallic ion but as a portion of a complex one. Thus, potassium ferrocyanide 
neither gives the chemical reaction of iron directly nor does it exert its physio- 
logical effects, for it is dissociated into potassium ions and ferrocyanide ions. 

Just as with the salts of the heavy metals, the disinfectant action 
of the acids is determined chiefly by their dissociability, for the dis- 
infecting power of their solutions in general runs parallel with the 
concentration of hydrogen ions on which their toxic action depends. 
The highly dissociable inorganic acids, such as hydrochloric, hydro- 
bromic, and sulphuric acids, are powerfully disinfectant, while phos- 
phoric acid is much less so. The organic ones, such as acetic, formic, 
and boric acids, are, however, far more strongly disinfectant than 
would be expected from the degree in which they are dissociated. As 
was demonstrated by Overton, the undissociated molecules of these 
ether-soluble acids are soluble in the lipoids, and consequently pene- 
trate into the bacteria more readily than the inorganic acids which 
are not soluble in these lipoids. 

In an entirely similar fashion a comparison of the disinfecting 
power of potassium and sodium hydroxide and of ammonia, as also 
of the hydroxides of lithium, calcium, strontium, and barium, shows 
that in general the value of the alkalies for disinfection depends 
on the percentage of free hydroxyl ions in their solutions. How- 
ever, here again the lipoid soluble ammonium hydroxide is an ex- 
ception, possessing, in spite of its slighter dissociability, more power- 
ful disinfectant action than corresponds to the concentration of the 
hydroxyl ions in its solutions. 

Phenol is but slightly ionized in solution, but this is of slight 
significance, for its antiseptic action is not due to the ion C G ILO, but 
to the undivided molecules. This essential difference explains the 
opposite influence exerted by the addition of salts on the disinfecting 
] lower of solutions of salts of the heavy metals and those of carbolic 
acid, for h is possible to decrease the degree of dissociation of electro- 
lytes by adding to their dilute solutions (in which dissociation is 
almost complete) another electrolyte possessing a common ion. Thus, 
a portion of the free me re ii ry ions in solutions of HgCl 2 may be forced 
bach into molecular combination by the addition <>!' NaCI, and in this 
way both the degree of dissociation and the disinfecting power of the 
.solution may be diminished. 



504 ETIOTROPIC PHARMACOLOGICAL AGENTS 

Disinfection Experiments with Anthrax Spores. 

Colonies develop- 
ing after 6 man. 
HgCta Concentration expos. 

HgCl 2 1 Mol. : 16 I 8 

HgCl 2 + NaCl 1 Mol.: 16 I 32 

HgCL + 2NaCl 1 MoL: 16 I 124 

HgCU + 4NaCl 1 Mol.: 16 I 382 

HgCl 2 + lONaCl 1 Mol.: 16 I 1087 

(After Paul u. Krunig) 

The disinfecting powers of solutions of carbolic acid are altered 
in an opposite direction by the addition of salt (Scheurlen) , for, in 
the ease of carbolic acid, the cresols, etc., the addition of salt 
markedly increases the disinfecting power of their solutions, this 
effect being produced not only by sodium chloride but by all salts. 
The augmentation of the disinfectant action runs parallel with the 
"salting out" power of the salts, for by this action the solubility 
of the carbolic acid in the water is diminished, and thus the partition 
coefficient between the medium and the cells is altered, so that the 
phenol penetrates into the bacteria in larger amounts than before 
(Spiro u. Bruns). 

Disinfection Experiments with Anthrax Bacilli 

Number of colonies after — 

Solution 1 day 3 days 5 days 

1% phenol 1520 1950 1650 

1% phenol + 24% NaCl 96 

2% phenol + 20% NaCl 1560 120 

3% phenol 1200 1120 1010 

3% phenol 4- 12% NaCl 

Influence of Surrounding Media. — From the above it may be 
concluded that the action of the antiseptics on bacteria is due to their 
chemical and physicochemical affinity to various constituents of the 
bacterial bodies. If these affinities find similar opportunities for 
chemical or physical combination with substances present in the 
complicated organic culture-medium, there results a rivalry between 
those constituents of the bacteria and those of the culture-medium 
which are capable of reacting with the disinfectants. Consequently it 
is clear that the efficiency of the antiseptics will depend not alone on 
their concentration and the duration of their action, but also on the 
chemical composition of the medium in which they act. Their full 
power can be exerted only in aqueous solutions, and their action is 
much weaker in culture-media which contain considerable amounts of 
organic substances, particularly proteids. Herein lies the almost in- 
surmountable difficulty which opposes a disinfection in the living body. 

Behring, for one, has shown that a twofold to fourfold higher concentration 
of corrosive sublimate is needed to kill spores in blood-serum than to do the same 
in distilled water. Anthrax bacilli in aqueous media are killed even by 1-500,000 
HgCl 2 , but in bouillon only by a concentration of 1-40,000, while in blood-serum 
with the same length of exposure even 1-2000 is no longer efficient. 



GENERAL ANTISEPTICS 505 

The influence of the medium expresses itself in different fashions 
according to the mechanism by which the antiseptic action is produced. 
It is particularly the proteid substances present in the secretions of 
wounds and in the tissue cells which divert the metallic ions away 
from the bacteria, and, as the albuminates form stable compounds 
with the salts of the metals, the antiseptic power of such solutions 
is permanently diminished in proportion to the amounts of the 
metals which combine with them. It is for the same reasons that 
iodine, which in a culture-medium containing but little proteid 
exerts a powerful disinfecting action, does so but feebly in the 
presence of much proteid. On the other hand, the antiseptic action 
of the ethereal oils which do not combine with proteids is much less 
impaired by them. 

BIBLIOGRAPHY 

Bokorny: Pfliiger's Arch., 1896, vol. 64, p. 262; 1905, vol. 10S, p. 216. 

Czapek: Biochem. d. Pflanzen, p. 857. 

Dreser: Arch. f. exp. Path. u. Pharm., 1893, vol. 32. 

Fischer, A.: Sitz.-Bericht d. kgl. Sacks. Ges. d. Wiss., 1891. 

Fischer, A.: Ztschr. f. Hvgiene, 1900, vol. 35. 

Geppert: Berl. klin. Woch., 1890, No. 11. 

Hober: Physikal. Chemie d. Zelle u. d. Gewebes, 2d edition, Leipzig, 1906, p. 261. 

Koch: Mitteil. aus dem kais. Gesundheitsamt, 18S6, vol. 1. 

Overton: Vierteljarhschr. d. Naturforscher-Ges. in Zurich, 1899. 

Overton: Pfliiger's Arch., 1902, vol. 92, p. 115. 

Paul u. Kronig: Ztschr. f. physik. Chem., 1896, vol. 12. 

Paul u. Kronig: Miinchn. med. Woch., 1897. 

Paul u. Kronig: Ztschr. f. Hyg., 1897, vol. 25. 

Scheuerlen: Arch. f. exp. Path. u. Pharm., 1895, vol. 37, p. 74. 

Spiro u. Brans: Arch. f. exp. Path. u. Pharm., 1898, vol. 41, p. 355. 

Spiro u. Scheuerlen: Miinchn. med. Woch., 1897. 

CONSIDERATION OF THE INDIVIDUAL ANTISEPTICS 
It will be sufficient for our purpose merely to name the more 
important antiseptics, and to discuss the actions of certain typical 
representatives of the different groups. The choice of an antiseptic 
will depend on the purpose for which it is to be used, certain of them 
being employed for the destruction of micro-organisms outside of the 
body, while others are used for the purpose of preventing their 
development in wounds and on mucous membranes. 

Chlorine is the most powerful and energetic disinfectant which 
we possess, but it also exerts a destructive action on all organic 
material. It is a yellowish-green gas, with a suffocating odor and 
very irritant to the mucous membranes, which, in the presence of 
moisture, is an extremely efficient disinfectant, most bacteria and 
their spores being killed by concentration of 3 per cent, of chlorine 
gas in the atmosphere. Bromine acts less energetically, and iodine 
still more weakly (Geppert, Paul u. Kromg). 

The employment of chlorine for the disinfection of various; ob- 
jects, living-rooms, etc., is very much limited by its destructive effect. 
"Where, however, this is of no importance, as in the disinfection of 



506 ETIOTROPIC PHARMACOLOGICAL AGENTS 

fa?ces, etc., one frequently uses chlorinated lime, a mixture of calcium 
hypochlorite, calcium chloride, and lime, which when treated with 
acids — on addition of HC1 — gives off free chlorine. A freshly pre- 
pared solution of potassium permanganate on the addition of 0.9 
per cent. HC1 also gives off free chlorine, which may be used for 
the disinfection of the hands (Paul u. Kronig). 

Chlorine water, Liquor chlori compositus, a yellowish-green, very 
irritating fluid, with a suffocating odor, containing 0.4 per cent, 
chlorine, is used as a corrosive and disinfectant in wounds and on 
mucous membranes, and was formerly employed as an intestinal dis- 
infectant. 

In the presence of water, chlorine oxidizes all organic material, 
for, by virtue of its strong affinity to hydrogen, it liberates nascent 
oxygen from the water. 

Even very small amounts of chlorine pas irritate the mucous membranes 
of the eye and nose, anil, if somewhat larger amounts are present in the atmos- 
phere, they cause the well-known protective reflexes, dyspnoea and coughing. 
When stronger concentrations are inhaled, they may cause bronchitis and pneu- 
monia. When chlorine is present in the air. its irritating effects may be dimin- 
ished by sprinkling ammonia about so as to form the now volatile ammoniurn 
chloride. 

BIBLIOGRAPHY 

Geppert: Berl. klin. Woch., 1S90. 

Paul u. Kronig : Ztschr. f. Hyg., 1897, vol. 25. 

Sulphurous acid, H 2 SO.„ whose gaseous anhydride, sulphur 
dioxide, S0 2 , is formed by the combustion of sulphur, is at present 
hardly used at all for the purpose of disinfecting residences. [Sul- 
phurous acid is the best — and in fact the only practical — means of 
killing the yellow- fever carrier, stegomyia fasciata, and in spite of 
its disadvantages it is used for this purpose, even in living-rooms. 
When thus employed all metallic objects and readily injured fabrics 
should, if possible, be removed from the room.- — Tr.] It is a 
powerful reducing agent, and, by virtue of this property, is an 
efficient means of preventing fermentation, and is used for this 
purpose in the preparation of wine casks. It is a particularly power- 
ful poison for moulds. 

Quicklime, CaO, is used as an inexpensive means of disinfecting 
large quantities of material, such as privy vaults or the stools of 
typhoid patients, etc. It acts as a bactericide by virtue of its dehy- 
drating power, and, after its transformation by the water into slaked 
lime, calcium hydrate, Ca(OH), as a powerful alkali destroys the 
bacteria. Finely powdered calcium hydrate suspended in water in a 
concentration of 20 per cent, is known as milk of lime, and its clear 
solution, containing about 0.17 per cent, of calcium hydroxide, is 
known as lime water. 

Crude mineral acids are adapted for disinfection en masse. 






GENERAL ANTISEPTICS 507 

Crude sulphate of iron acts chiefly as a deodorizer by virtue of 
its power of combining with sulphuretted hydrogen and ammonium 
sulphide. 

Formaldehyde is an extremely valuable disinfectant for in- 
animate objects. It is a colorless gas which is very irritant to the 
conjunctiva and nasal mucosa, and when dissolved in water is 
a very powerful antiseptic and also a sufficiently powerful bacter- 
icide. Anthrax bacilli are killed in one hour by a dilution of 1 to 
2000 and their spores by 1 to 1000. This drug readily penetrates 
into the bacterial bodies, and reacts with numerous organic sub- 
stances and in particular coagulates proteid. It is very irritant to 
animal tissues, but after absorption is relatively non-toxic to the 
central nervous system, as it is almost completely decomposed in the 
body, only a small portion being excreted as formic acid. Another 
small portion is probably excreted in unaltered form, as after in- 
gestion of formaldehyde the urine is weakly antiseptic. Used ex- 
ternally formaldehyde hardens or tans the skin, and consequently 
sweat secretion may be diminished by bathing the skin with its 
solutions. Formaline or formol is a 40 per cent, (by volume) aqueous 
solution of formaldehyde. 

In y 2 to 1 per cent, aqueous solutions formaldehyde is used for 
the disinfection of mucous membranes, but it is chiefly employed for 
the disinfection of residences, etc. Generated with steam and in- 
troduced into hermetically closed rooms, formaldehyde produces a 
reliable surface disinfection, for in gaseous form it reaches the 
surfaces of all the objects which are to be disinfected, and is de- 
posited on them dissolved in extremely small drops of water. How- 
ever, this method of disinfection does not exert any considerable 
disinfection except on the surface of the various objects. When the 
rooms are opened again the suffocating and irritating formaldehyde 
vapor and odor may be removed by the use of ammonia vapor, which 
combines with formaldehyde forming the non-volatile hexamethyl- 
enamine. 

In disinfection of the skin, either that of the hands of the 
operator or the skin of the field of operation, the greatest emphasis 
is at present laid upon an energetic mechanical cleansing, which 
should be followed by a chemical disinfection in order to lessen 
aa far as possible the number of germs hidden in the pores and 
glandular canals of the skin. Although complete freedom from such 
germs c;mnot be obtained, alcohol and corrosive sublimate have been 
shown by bacteriological investigation of disinfection of the hands 
to be the besl substances for this purpose (Paid u. Sarwey). Even 
in a concentration ol* 5 per 10 per cent, ethyl alcohol inhibits the de- 
velopment of bacteria, but its disinfecting power increases with its 
concentration only up to a certain fixed point, and absolute alcohol 
exerts very Blight disinfecting actions. In the strength of 50 per cent. 



508 ETIOTROPIC PHARMACOLOGICAL AGENTS 

it occupies a position midway between 1-1000 corrosive sublimate 
and 3 per cent, carbolic acid. 

In the disinfection of the hands, in addition to its bactericidal 
power, alcohol's property of dissolving the fatty skin secretions is of 
considerable importance, as is its power of penetrating, the skin, by 
virtue of which property it is able to attack the bacteria in the 
deeper layers of the skin and to open the path for other disinfectants 
which may be used later (Fiirhringer, Ahlfeld, Mikidicz). 

BIBLIOGRAPHY 

Ahlfeld: Monatschr. f. Get), u. Gyn.. 1899, vol. 10. 

Fiirbringer: Deut. med. YVoch., 1899, No. 49. 

Mikulicz: Deut. med. Woch., 1899, No. 24. 

Paul u. Sanvey: Miinehn. med. Woch., 1899, No. 51; 1901, No. 36. 

The disinfection of instruments and other objects, particu- 
larly those which may come in contact with wounds, may be accom- 
plished by the use of 3 to 4 per cent, carbolic acid solutions, by lysol, 
and by other aromatic antiseptics, as also by 1 to 1000 sublimate 
solutions, which latter should not be used on metal instruments as 
they form amalgams with the metals. The same substances in weaker 
concentrations are also used in wounds as antiseptics. 

In the disinfection of mucous membranes and wounds the use 
of higher concentrations of the stronger disinfectants is contraindicated, 
by the unavoidable damage to the tissues produced by these general 
cell poisons and by the danger of systemic poisoning from their 
absorption. While the antiseptics cause actual destruction of the 
tissue only in concentrations considerably stronger than those which 
prevent the development of bacteria, these drugs are all general 
cell poisons, and, even in very weak solutions, impair the vital 
functions of the tissues and thus interfere with their natural pro- 
tective reactions and consequently prepare a favorable culture- 
medium for bacteria. 

It is for this reason that the modern surgeon has given his pre- 
ference to aseptic measures and has correctly abandoned the employ- 
ment of antiseptics in the treatment of wounds. Even for the 
purpose of cleansing already infected wounds, the methods formerly 
commonly employed in the attempt to secure energetic disinfection 
have been abandoned, and to-day, in place of 1-1000 bichloride or 
3 per cent, phenol or lysol solutions, much weaker solutions or milder 
antiseptics, like hydrogen peroxide, aluminum acetate, or boric acid, 
are employed for the purpose of cleansing wounds of their germs. 
These weaker concentrations are scarcely able to inhibit the develop- 
ment of bacteria, and perhaps in the treatment of wounds play only 
the role of sterile cleansing fluids. 

Moreover, in view of the rapidity with which bacteria multiply, 
it would not be possible to obtain a radical purification of wounds 
even by the use of the stronger concentrations (Schimmelbusch) , and 



GENERAL ANTISEPTICS 509 

the damage done to the tissue cells by such procedures would en- 
danger the healing of wounds, which, as a rule, are able by them- 
selves to destroy the invading bacteria. A destruction of bacteria 
within the tissues of the human body by general — that is, by non- 
specific — disinfectants is possible only in those cases in which one 
is willing to accomplish this at the cost of the sacrifice of tissue cells 
which are capable of regeneration, and consequently is of slight 
value. Examples of this would be the application of the tincture of 
iodine to the skin for the purpose of making an incision through 
tissues which are certainly free of bacteria, or the treatment of 
diphtheria by the local application of caustics for the purpose of 
killing the bacilli at the same time with the tissues. 

The employment of antiseptics in wounds and mucous membranes, 
as has already been mentioned, is still further limited by the danger 
of systemic poisoning as a result of their absorption. This may be 
prevented if the distoxication of the antiseptic — by its elimination or 
chemical transformation — keeps pace with its absorption and thus pre- 
vents the attainment in the blood of a toxic threshold value. Theo- 
retically this indication is best met by hydrogen peroxide, which, as 
soon as it comes in contact with the tissues, is decomposed into water 
and oxygen. Unfortunately, at the same time its local disinfecting 
power is diminished. 

Formaldehyde and potassium permanganate also cause only local 
damage to the tissues and no harmful systemic effects. Unfortu- 
nately, the most reliable antiseptics, bichloride, carbolic acid, etc., 
owing to their lipoid solubility are readily absorbed. Perhaps it would 
be worth while to try and see if, like cocaine, they could be retained 
longer at the point of application by the addition of epinephrin to 
their solutions, and if the absorption of sufficiently concentrated solu- 
tions could be thus retarded. 

As a rule, when toxic quantities of toe general cell poisons are absorbed, 
it is the central nervous system which is most affected, and after it the organs 
of elimination, as during their elimination these poisons accumulate in these 
cells in somewhat high concentrations. 

BIBLIOGRAPHY 
Schimmelbusch: Fortschr. d. Med., 1805. 

Boric acid, II :i BO : „ is soluble in 20 parts of water at ordinary 
temperatures. Solutions of 1 to 3 in 100 are simply antiseptic and 
not bactericidal. As this weakly dissociated acid produces hardly 
any corrosive effect, it does not damage the tissues, and may be ap- 
plied to surfaces of wounds and even such mucous membranes as 
the conjunctiva, or be used to wash out the stomach, the bladder, 
the uterus, etc. However, it must not be forgotten that boric acid is 
by no means lacking in toxicity, for in larger doses it causes gastro- 



510 ETIOTROPIC PHARMACOLOGICAL AGENTS 

intestinal irritation, and, when considerable amounts of its solutions 
have been left in body cavities, it has in a number of cases caused 
fatal poisoning. 

Borax, biborate of soda, Xa 2 B 4 7 -f- 10H 2 O, by virtue of its weak 
elective reaction, acts somewhat antiseptieally, and is particularly 
effective against moulds and yeast-fungi, and is consequently used in 
the treatment of thrush. 

Boric Acid and Borax as Preservatives for Food. — As a con- 
sequence of their relative lack of toxicity, boric acid and borax have 
been widely used as preservatives for meats, sausages, preserves, and 
so forth. Borax is also, though improperly, used as a preservative 
for milk, in which it, like all alkaline salts, impairs the coagulability 
of casein. The presence of either of these substances in food is not 
betrayed either by taste or smell, but in order to be effective they must 
be added in amounts ranging from 5 to 30 parts in the thousand. 
Consequently, as they are so generally employed for the preservation 
of our most important food-stuffs, it is possible that as much as 
several grammes may be ingested daily, and such doses when taken 
continually are by no means harmless, particularly inasmuch as boric 
acid is slowly excreted, and consequently can accumulate in con- 
siderable amounts in the organism. 

According to the investigations of Host, Rubner, and others, even 
daily doses of 0.5 to 1.0 gm. of boric acid exert a deleterious effect 
upon the utilization of the food, and augment the combustion of 
nutrient material, particularly that of non-nitrogenous substances, 
such as fat. Even in healthy individuals considerable loss of weight 
results after 5-12 days from the administration of 0.3 gm. daily, 
and in nephritic patients, in whom its excretion is retarded, the 
harmful results may be even more serious. These facts entirely 
justify the prohibition of its use as a preservative for food. 

BIBLIOGRAPHY 

Rost: Arb. aus d. kais. Gesundlieitsamt, 1902, vol. 19. 

Host: Deut. med. Wocb., 1903, No. 7. 

Rost: Arch, intern, de Pharmacodynamic, 1905, vol. 15. 

The sulphites also, particularly sodium sulphite, are much used 
as preservatives for meat in amounts which often reach to 4 to 20 
parts per 1000. Although large doses of sulphites can produce gen- 
eral harmful effects (Pfeiffer, Post), in view of the rapid and almost 
complete transformation of the sulphites into the harmless sulphates 
(Franz u. Sonntag), it is still an open question whether the amounts 
necessary for the preservation of food-stuffs are sufficient to cause 
harmful effects. 

[Even Wiley's own figures obtained in his experiments with the 
famous "poison squad," when carefully examined, fail to support 
his claim that the sulphites, in moderate amounts, are deleterious. — 
Tr.1 



GENERAL ANTISEPTICS 511 

BIBLIOGRAPHY 

Franz u. Sonntag: Arb. aus d. kais. Gesundheitsamt, 1908, vol. 28, p. 225. 
Pfeiffer: Arch. f. exp. Path. u. Pharm., 1890, vol. 27, p. 261. 
Host: Arb. aus d. kais. Gesundheitsamt, 1904, vol. 21. 

Hydrogen Peroxide. — Oxidizing agents, by liberating nascent 
oxygen, act as disinfectants in a fashion fundamentally similar to 
chlorine. Hydrogen peroxide, which is decomposed with extreme 
readiness into water and oxygen, is the most powerful of these agents 
which may be employed in medicine. In aqueous solution it is de- 
composed with a very active liberation of oxygen by catalase, a 
ferment present in all cells, and also by many inorganic substances 
which in a state of very fine subdivision act like ferments. 

This nascent oxygen acts as a disinfectant, but, as the action 
is limited to the short period during which the gas is generated, it 
can act only momentarily and superficially. This substance is suit- 
able for use as a mouth-wash or gargle, or as a means of moistening 
dressings, for nascent oxygen destroys disagreeable-smelling and 
toxic decomposition products. 

When injected into closed body cavities, such as the peritoneal cavity, 
hydrogen peroxide in unaltered form may enter the blood and cause sudden death 
as a result of the generation of gaseous oxygen in the blood. 

Ferments, too, are rapidly destroyed by hydrogen peroxide. Its employment 
as a preservative for milk prevents souring, but at the same time destroys the 
enzymes and antitoxic substances normally present in milk. 

Potassium permanganate, KMn0 4 , also acts as an oxidizing 
agent, which is very readily reduced by proteid as well as. by all 
other labile organic substances. The manganese oxide, which re- 
sults from this reduction, forms a brown precipitate, causing brown 
spots on the skin and elsewhere. Even 1 per cent, solutions cause 
a caustic action on the surfaces of wounds and mucous membranes, 
but in a concentration of 1 to 1000 it deodorizes foul-smelling putre- 
faction products and exerts a weak disinfectant action. It may 
consequently be used for the washing of wounds and mucous mem- 
branes or as a mouth-wash, etc. 

In this connection, mention should lie made of the employment of potassium 
permanganate as an antidote in poisoning by phosphorus, morphine, and other 
toxic BUbstances, which are readily oxidized and rendered non-toxic, but benefit 
may be expected from its employment only if these poisons are still present in 
the stomach. Potassium cyanide also is transformed by it into the less toxic 
potassium cyanate. 

Potassium chlorate, KCIO.,, is weakly antiseptic by virtue of 
its oxidizing powers. When heated, it oxidizes so energetically that, 
when mixed with readily combustible substances, an explosion may 
result from such slight warming as is produced by their trituration 
in a mortar. In the body it, gives off its oxygen very slowly and is in 
largest part (about 00 per cent.) excreted in Hie urine. Even in 
strong concentrations it hardly inhibits the growth of bacteria, and 



512 ETIOTROPIC PHARMACOLOGICAL AGENTS 

consequently it is questionable whether, when used as a gargle, it 
acts better than solutions of indifferent salts. Formerly curative 
effects in diphtheria were attributed to its action after absorption, 
and even now it is administered in doses of 4 to 6 gm. per diem in 
pyelitis and cystitis, with the idea that it endows the urine with 
antiseptic properties. Its internal administration in doses of more 
than 8 gm. per diem [or in much smaller doses. — Tr.] is under 
all circumstances attended by great danger, and with impaired 
renal function even smaller doses are dangerous (Quincke). 

After absorption potassium chlorate penetrates into the red blood-cells 
with relative ease and transforms the haemoglobin into methaemoglobin, so that 
the blood acquires a brownish color and the spectroscope shows a characteristic 
narrow stripe in the red portion of the spectrum. When this action is pro- 
duced in a sufficient degree, all the symptoms of methaemoglobinaemia result (see 
p. 451). In very acute cases internal asphyxia results and death occurs in a few 
hours. In somewhat more protracted cases hemorrhages, diarrhoea, vomiting 
of greenish-black material, and all the other results of the destruction of the 
red cells occur. Agglutination of the red cells occurs, causing thrombi, infarcts, 
and ecehymoses, and the broken-down cells are deposited in the organs which 
normally destroy them, while the liver and spleen become swollen and jaundice 
develops. 

The urine acquires a reddish-brown to black color and contains proteid, 
broken-down red cells, methaemoglobin, and hseniatin, and, as a result of blocking 
of the renal tubules, anuria and death with ursemic symptoms result. Doses 
which exceed 10 gm. can cause severe poisoning, while 15 to 20 gm. are, as a 
rule, fatal. The treatment can consist only in stimulation of diuresis to 
accelerate the elimination of the poisons, but bleeding and saline infusions are 
also recommended. 

As in various infectious diseases the red blood-corpuscles have to 
some extent become more permeable to various salts, the internal ad- 
ministration of potassium chlorate in these conditions is contrain- 
dicated, just as it is in nephritis. Moreover, the use of large quan- 
tities of potassium chlorate solutions as a gargle has often caused 
serious poisoning, particularly in children, as a result of the unavoid- 
able swallowing of the drug. 

BIBLIOGRAPHY 

Quincke: Deut. Arch. f. klin. Med., 1904, vol. 79, p. 290. 

MERCURIAL SALTS 
In vitro the soluble and dissociable mercury compounds are power- 
ful disinfectants, but the proteids present in wound secretions very 
markedly lessen their disinfecting power. Corrosive sublimate, the 
bichloride of mercury, HgCL, which is soluble in 17 parts of cold 
water, and the other soluble mercuric salts damage the cells of the 
tissues even in those low concentrations which prevent the develop- 
ment of bacteria. Moreover, the employment of larger quantities of 
even dilute solutions of these salts is limited by the danger of their 
absorption, which is especially great when they are used for wash- 
ing out large wounds or mucous membranes. 



GENERAL ANTISEPTICS 513 

Bichloride of mercury with proteids forms albuminates which 
with an excess of proteid and sodium chloride form soluble double 
salts of mercury albuminate and NaCl. As a consequence, the coagu- 
lum at first formed by their local action soon goes into solution and is 
absorbed, and, as a result, numerous acute and subacute mercurial 
poisonings have occurred, particularly after the postpartum use of a 
bichloride solution as an intra-uterine douche. 

For the purpose of preventing the formation of insoluble mercury 
albuminates, sodium chloride is added to bichloride solutions, many 
of the bichloride tablets containing this salt, although the disin- 
fectant power is impaired by this addition. Recently, in place of 
the sublimate a compound of mercuric sulphate with ethylenediamine 
has been recommended under the name of sublamine, which, being 
a complex mercuric salt, does not precipitate proteid or cause irrita- 
tion of the tissues. 

Mercurial Poisoning. — When large quantities of mercury are rapidly 
absorbed, the systemic effects are exerted principally on the central nervous 
.system and the organs of elimination, in this case chiefly the large intestine 
and the kidneys. As a result of the accumulation of relatively large amounts 
of mercury in the cells through which this metal is excreted, these cells undergo 
necrosis, and nephritis and colitis result, the latter causing abdominal pain, 
tenesmus, and diarrhoea containing blood and shreds of the mucous membranes. 
The toxic action on the central nervous system expresses itself in a condition 
of stupor or apathy and finally by collapse, as a result of which the patient 
dies with a subnormal temperature usually only after 5-10 days. Post mortem 
one finds hemorrbagic diphtheritic inflammation of the caecum and colon and 
parenchymatous nephritis, often with calcium infarcts in the kidneys, as a 
result of tlie deposition of calcium phosphate and carbonate in the necrotic renal 
epithelium. When rapidly absorbed, 0.1 gm. of bichloride may produce fatal 
poisoning. The maximal dose of the soluble mercuric salts is 0.02 gm. per dose, 
0.06 gm. per diem. 

In less acute cases the first symptoms noted are those of the mercurial 
stomatitis, salivation, metallic taste, and disagreeable odor in the mouth, with 
redness and swelling of the gums and tongue. In such cases the symptoms due 
to intestinal and renal lesions appear only some days later. The accumulation 
of mercury in the body as a result of its long-continued administration and 
chronic mercury poisoning are described on pages 415 and 542. 

Silver salts. — The dissociable and soluble silver salts are also 
very strongly antiseptic, preventing the development of many 
bacteria even in the blood-serum and in a dilution of 1 to 80,000. 
Silver lactate (actol) and silver citrate (itrol) are preferred by some 
surgeons to corrosive sublimate. 

Silver mimic in different concentrations is used for the disin- 
fection of mucous membranes, — for example, in 2 per cent, solution 
as a means of preventing ltd norrl Heal ophthalmia in the new-horn, 
and in 2-4 per cent, solutions in the treatmenl of urethral gon- 
orrhoea.* Eowever, when thus used its adion is confined to the 

•[The a trii at and disinfectant actions of silver i pounds do nol 

account entirely for their almost specific effects in gonorrhoea! inflammations. 
It is highly probable that they owe much of their curative action to their power 
of attracting the Leucocytes w them, — i.e., to their cbemotacic powers. — Tb.] 

33 



514 ETIOTROPIC PHARMACOLOGICAL AGENTS 

surface of the mucous membranes, as silver combines with proteid and 
sodium chloride. As the organic silver compounds do not directly 
combine with proteid and XaCl, such compounds as protargol, a solu- 
tion of an albuminate of silver, argonin, a compound of silver with 
casein, and arc/ cut a mine, ethylenediamine silver phosphate, exert a 
more penetrating action. 

In man systemic poisoning as a result of the absorption of silver does 
not occur, but after the long-continued use of silver compounds a peculiar 
grayish discoloration of the skin and of various internal organs results from 
the deposition in these tissues of insoluble metallic silver, a condition to 
which the name of argyria is given. 

The essential action of the salts of copper, zinc, and lead is that 
of astringents and corrosives. Aluminum acetate exerts both 
astringent and antiseptic actions, and has once more come into use 
as a mild antiseptic in the treatment of wounds. 

ANTISEPTICS BELONGING TO THE AROMATIC GROUP 
Numerous aromatic substances which are sufficiently soluble in 
water to reach the cells, and sufficiently soluble in lipoids to penetrate 
them readily, possess antiseptic and disinfectant properties, but in 
stronger concentrations they kill the cells of the tissues and when 
absorbed are typical nerve poisons. Among these the most efficient 
are the various phenols and their ethers (Laubenheimer) . As the 
aromatic hydrocarbons are less powerful than the phenols, benzol 
is a feebler antiseptic than carbolic acid, toluol than the creosols, 
naphthalin than the naphthols, etc. This is probably to be explained 
by their slighter solubility in water. The toxicity of the phenols does 
not increase with the number of hydroxyl groups, the bivalent phenols, 
brenzcatechin, hydroquinone, and resorcin, being less toxic than car- 
bolic acid. The substitution of acid radicals for hydroxyl groups, as 
also the introduction of acid groups in any position in aromatic 
molecules, markedly lessens their activity. In spite of this, free 
aromatic acids, benzoic acid, salicylic acid, etc., are antiseptic and 
cytotoxic, but their neutral salts, which are insoluble in the lipoids 
and which consequently are unable to penetrate cells rapidly, are not. 

Fate in the Body. — Inasmuch as in the organism the benzol ring, as a 
rule, remains intact, the fate of the aromatic substances in the organism differs 
from that of substances of the aliphatic series. In general, the aromatic com- 
pounds, after undergoing oxidation or losing some of their radicals, enter into 
synthetic combination with various intermediary metabolic products and form 
non-toxic substances. Thus, the phenols are conjugated in the liver with sul- 
phuric and glycuronic acids, and many of the aromatic acids are combined in the 
kidney with glycocoll, the halogen substituted benzols, for example, combining 
with glycocoll and forming mercapturic acids. 

Phenol, C 6 II 3 OH, or carbolic acid, is the type for the whole 
group. It occurs as colorless crystals, with a characteristic pene- 
trating odor, which on exposure to air turns pink. It is soluble in 20 



AROMATIC ANTISEPTICS 515 

parts of water and is readily soluble in the lipoids, so that it readily 
penetrates into all tissues. In concentrations ranging from 1-200 
to 1-30, it is a very efficient bactericide, killing most bacteria, but 
spores are extremely resistant to it. It was carbolic acid which 
was used by Lister when he introduced the antiseptic method into 
medicine, and in the antiseptic era it played a far more important 
role than at present, for it has in large part been replaced by similar 
antiseptics, but more particularly because to-day chemical disin- 
fectants are employed only to a limited extent in the treatment of 
wounds. 

Local Action. — Concentrated solutions of carbolic acid are power- 
fully corrosive, and when applied to the skin cause a white eschar, 
which later turns red and then brown, and which is finally cast off 
without the formation of pus. Even 5 per cent, solutions cause burn- 
ing and pain and later local anaesthesia. More dilute solutions also 
can irritate the skin or on longer contact cause necrosis. Conse- 
quently, as carbolic acid readily penetrates the skin, dressings 
moistened with 2-3 per cent, carbolic acid, if left in place for a con- 
siderable time, may cause dry gangrene of the fingers and toes. 

Toxicology. — This drug is rapidly absorbed wherever applied, 
even through the skin, and its systemic action is exerted chiefly on 
the central nervous system. In animals poisoned by it, at the start 
symptoms of excitation of the medullary and spinal centres pre- 
ponderate, but in man, when poisonous amounts are absorbed, paraly- 
sis of the central nervous system occurs, usually without preceding 
convulsions. As even 1 to 2 gm. can produce poisoning and as 3 to 10 
gm. are usually fatal, the maximal dose for internal administration 
should be 0.1 gm. 

Poisoning with carbolic acid usually occurs as a result of suicidal 
attempts or of mistaking liquefied carbolic acid for more dilute solu- 
tions.* When concentrated solutions or the pure acid are swallowed, 
corrosion of the mucous membranes like that produced by concentrated 
mineral acids results, but in addition, because of the extreme rapidity 
with which absorption occurs, the local symptoms are quickly ob- 
scured by those of the systemic poisoning and very quickly, usually 
after a few minutes, the patient becomes completely unconscious and 
falls into a state of profound collapse. 

When absorbed Erom the rectum or from the uterus, as may occur 
with its careless use post-partum, even relatively small amounts of 
carbolic acid may produce severe systemic poisoning, for in these 
cases the poison passes directly into the general circulation without 
first going through the liver. For the same reason, carbolic acid is 
distinctly more toxic when absorbed through the skin. 

In former times, when carbolic acid was much more widely used 
in surgery, less acute carbolic acid poisoning was frequently ob- 

■ Carbolic acid liquefied by the addition of 10 per cent, of water. 



516 ETIOTROPIC PHARMACOLOGICAL AGENTS 

served, beginning with vertigo, headache, a tipsy stupor, and vomit- 
ing, and in more serious cases frequently causing cold sweats, 
cyanosis, and small frequent pulse, with collapse and marked fall of 
the body temperature. 

In such cases the process of distoxication proves inadequate, although 
ordinarily by the formation of conjugated sulphuric and glycuronic acids the 
organism can render even considerable amounts of carbolic acid harmless, provided 
they are gradually absorbed. As a portion of the carbolic acid is oxidized in the 
organism to dioxybenzols and is excreted in the urine chiefly in the form of 
hydroquinone-sulphuric acid, and as in the urine this substance is readily trans- 
formed into greenish-brown to black oxidation products, the urine, when car- 
bolic acid has been absorbed in considerable amounts, gradually acquires a dark 
color on standing or is already discolored when passed. When too large amounts 
have been absorbed, both carbolic acid and the dioxybenzols are excreted without 
undergoing conjugation, and may cause albuminuria and nephritis. 

Treatment of Carbolic Acid Poisoning. — When the poison has 
been taken by mouth, the most important indication is to wash out 
the stomach immediately, and, if this is done quickly enough, the 
corrosion caused by the poison — in contradistinction to that caused 
by concentrated acids, alkalies, etc. — may heal without leaving serious 
results. [A 15-20 per cent, solution of alcohol should, whenever pos- 
sible, be used in washing out the stomach in these cases. — Tr.] 

Saccharated lime has also been recommended as an antidote, as this 
forms an insoluble calcium carbolate. Both animal experiments and 
clinical experience have demonstrated the futility of administering 
sodium sulphate with the idea of augmenting the synthesis of ethereal 
sulphuric acid and thus rendering the absorbed phenol non-toxic 
(Tauber, Marfori). 

Sulphocarbolatcs. — If carbolic acid be dissolved in concentrated sulphuric 
acid, sulphocarbolic acid is formed, which is far less active than carbolic acid 
itself. The iodized parasulphocarbolic acid has been introduced commercially 
under the name of sozoiodolic acid, and has been used in the form of its zinc salt 
in the treatment of gonorrhoea and in the form of its mercurial salt in the treat- 
ment of lues. However, in all probability these compounds possess no advantage 
over other zinc and mercury salts. 

The Cresols. — Next to carbolic acid the cresols are the most 
important aromatic disinfectants. For a long time it has been the 
custom to use for disinfection on a large scale, in place of the ex- 
pensive pure carbolic acid, the cheaper raw acid which remains after 
pure carbolic acid has been extracted from coal-tar. In addition 
to other products obtained from coal-tar by dry distillation, such 
as naphthaline, pyridine, etc., this raw carbolic acid contains three 
isomeric cresols, homologues of phenol, in which a methyl radical re- 
places a hydrogen atom in the ortho-, meta-, and para-positions. 

OH OH OH 

/\CH, /\ ,/\ 



CH 3 

Metaoresol 



CH 3 



AROMATIC ANTISEPTICS 517 

The powerful disinfectant action of these cresols was quickly 
recognized, but their insolubility rendered their utilization as disin- 
fectants difficult. An impure mixture of these three isomers is known 
as crude cresol or tricresol, while creolin is an emulsion of cresols and 
hydrocarbons of uncertain and varying composition. In the form 
of solutions of their alkaline soaps, the cresols have been widely 
used, lysol and the liquor cresolis compositus being such solutions 
which contain about 50 per cent, of cresol. Many similar prepara- 
tions may be obtained under different names. For gross disinfection 
quite extensive use has been made of saprol, which is a mixture of 
80 parts of crude carbolic acid and 20 parts of petroleum, and which, 
because of the presence of the lighter hydrocarbons, floats on the 
materials to be disinfected and covers them over with a thin coat- 
ing, from which the cresols, etc., gradually permeate the whole 
mixture. 

Formerly it was thought that these cresols were less toxic than 
carbolic acid, but, as a matter of fact, when absorbed, they are by 
no means less toxic. Among themselves, however, they are not equally 
toxic, metacresol being the weakest, and paracresol for many species 
of animals almost twice as toxic, while orthocresol lies between 
(Wandel, Tollens). "While the cresols are more powerfully antiseptic 
than phenol, it is practically of greater importance that, on account 
of their slighter absorbability, they are, in proportion to their dis- 
infecting power, relatively less toxic. 

"When absorbed, the cresols produce the same toxic systemic ef- 
fects as carbolic acid (Eochmann). Suicide by swallowing lysol has 
been particularly common in recent years, and causes the same un- 
consciousness and collapse as does carbolic acid, the only difference 
being that in these cases convulsions appear to occur more frequently 
than in carbolic acid poisoning. The treatment of such poisoning 
is the same as that of carbolic acid poisoning. 

In cresol poisoning also, the urine becomes dark colored (Matter), and 
nephritis occurs. The cresols are excreted with the bile (Wandcl, Bial) , and 
may cause parenchymatous hepatitis. 

Thymol. — Of the higher homologues of phenol, thymol, methyl- 
isopropyl phenol, is a more powerful antiseptic than carbolic acid or 
the cresols. It is very insoluble in water — 1 to 1000 — and is con- 
sequently absorbed with difficulty, and may, therefore, be used as a 
relatively non-toxic antiseptic wash. 

Of the dioxybenzols, resorcin, metadioxybenzol, is used in the 
treatment of diseases of the skin and as an antiseptic wash and has 
also been used internally. 

Pykogallol, or pyrogallic acid, trioxybenzol, is a powerful reduc- 
ing agent which is used in the treatment of psoriasis and other 
parasitic diseases. It is very irritant or even corrosive and stains 
the skin black, and, as it is also readily absorbed, is a. powerful poison 
to the blood, reducing oxyhemoglobin to methsemoglobin. 



518 ETIOTROPIC PHARMACOLOGICAL AGENTS 

In the treatment of skin diseases, use is also made of chrysarobin, 
naphthaline, and beta-naphthol, as also of the various tars obtained 
by the distillation of wood, such as pix liquida, which contains phenol 
and various other esters, and also terpenes and resinous acids, or the 
purified tar, anthrasol. 

Ichthyol, a vile-smelling mixture containing 10 per cent, of sul- 
phur, which is obtained by the distillation of bituminous rocks from 
the Tyrol containing fossil fishes, is used for similar purposes. 

Balsam op Peru is an antiseptic agent which irritates the tissues 
but slightly. It occurs as a thick brown liquid, and is a mixture of 
40-60 per cent, of the benzylester of cinnamic acid, 10 per cent, of 
free cinnamic acid, and various resins. Even this relatively non- 
toxic antiseptic, however, when absorbed in considerable quantities, 
like all the above-mentioned antiseptics, can and does cause damage 
to the kidneys.* 

Finally, salicylic acid (ortho-oxybenzoic acid) is a powerful anti- 
septic, hardly exceeded in its activity by phenol, which, however, is 
almost insoluble in water. On the skin it exerts a keratolytic and an- 
tisudorific action, and on mucous membranes it is irritant or cor- 
rosive. Its salts are only feebly antiseptic and are not corrosive. For 
its employment as an internal disinfectant see page 530. 

BIBLIOGRAPHY 

Bial: Arch. f. exp. Path. u. Pharm., 1907, vol. 56, p. 416. 
Kochmann: Arch, intern, de Pharmacodyn., 1905, vol. 14, p. 401. 
Laubenheimer : Phenol and s, derivate, Wien and Berlin, 1909. 
Marfori: Archivo di Farmacol. e Terapia, 1894, vol. 2. 
Matter: Hofmeister's Beitrage zur chem. Physiol., 1907, vol. 10, p. 251. 
Tauber: Arch. f. exp. Path. u. Pharm., 1895, vol. 36, p. 197. 
Tollens: Arch. f. exp. Path, u, Pharm., 1905, vol. 52, p. 220. 
Wandel: Arch. f. exp. Path. u. Pharm., 1907, vol. 56, p. 161. 

Iodoform. — "While the treatment of wounds by antiseptic solu- 
tions has constantly gone more and more out of fashion, iodoform 
is still widely used as an antiseptic dusting powder, although much 
less freely than formerly. Its value lies in the fact that it is very 
insoluble, and consequently, without causing damage to the tissues, 
remains as a harmless reserve store from which an actually effective 
substance or substances are gradually split off under the influence of 
the secretions of the wound. It occurs as a yellow crystalline powder, 
with a characteristic disagreeable and penetrating odor, and is 
almost insoluble in water, but readily soluble in fats and ether. It is 
much used in the treatment of purulent sinuses and ulcers, and with 
particularly good effect in tubercular conditions. In vitro it is very 
feebly bactericidal, even tubercle bacilli, like most other bacteria, being 
unaffected even when exposed for weeks to iodoform vapor. On the 

* [A temporary albuminuria of considerable severity often follows the ex- 
ternal application of balsam of peru in the treatment of scabies. — Tr.] 



IODOFORM 519 

other hand, cholera vibriones are relatively quickly killed by it 
(Baumgarten, Troje u. Panke). On the surface of wounds it gradu- 
ally goes into solution, and from this solution iodine is slowly and 
continually liberated, exerting an antiseptic and deodorizing action 
on the wound secretions. As iodine is chemically extremely active, 
it acts upon all the chemical labile organic substances present in the 
secretions of the wound, and in this fashion destroys putrefactive 
substances and probably also renders various toxins harmless * 
(Behring) . This mild iodine action, resulting from its slow liberation, 
also acts as a mild stimulant for the formation of granulations in 
tubercular lesions, etc. 

Toxicology of Iodoform. — The iodine liberated from iodoform is 
absorbed partly as an albuminate, or in the form of other organic 
compounds, and in part as iodides of the alkalies, and is excreted 
in the urine in part as inorganic iodides and in part in organic 
combinations of still unknown nature. Consequently, iodoform, like 
the alkaline iodides, may cause general iodine effects, such as coryza 
and acne (see p. 400). However, iodoform is also absorbed un- 
changed, for the acute iodoform poisoning, occurring when it is ab- 
sorbed in too large amounts, differs very essentially from the toxic 
effects produced by inorganic iodine compounds. Such poisoning 
develops slowly, the first symptoms noted being those of vague dis- 
turbances of the central nervous system, which are followed, after 
several days, by conditions of mental excitement, hallucinations, and 
delirium, alternating with confusion and stupor, but in some cases 
the poisoning resembles a pure narcosis. These symptoms of poison- 
ing are due to the absorption of iodoform in a form which is neuro- 
tropic, Loeb having been able to find iodine in the brain after the 
administration of iodoform and other lipoid soluble organic iodine 
compounds, although even after the administration of large quan- 
tities of organic iodides no iodine could be found there. When 
absorbed by the cells of the brain, iodoform acts as a narcotic in the 
same fashion as other lipoid soluble indifferent substances ; but, 
as its absorption into, and particularly its elimination from, the brain 
occurs much more slowly than does that of the closely related chloro- 
form, its action often lasts for days or weeks. In such cases, just 
as after chloroform, fatty degeneration of parenchymatous organs 
occurs. 

The treatment for iodoform poisoning can consist only in its 
immediate removal from the situation from which it is being ab- 
sorbed. However, owing to the firmness with which it is combined 
with the nerve-cells, the unfavorable course of the poisoning cannot 
always be prevented by such measures. 

Iodoform Substitutes. — The extremely diBagreeabl lor of iodoform has 

led to the introduction of numerous substitutes, chiefly iodized aromatic com- 

* According <<> Heile, under these conditions other soluhle decomposition 
products eontiiinintf iodine arc formed, which produce an antiseptic effect. 



520 ETIOTROPIC PHARMACOLOGICAL AGENTS 

pounds which are themselves antiseptic and which are also supposed to liberate 
iodine in the tissues, but none of these substitutes has proven equally efficient 
with iodoform. It appears that benzol derivatives, such as Loretin (iodoxy- 
quinolinesulphonic acid), Nosophen (tetraiodophenolphthalein), Losophan (tri- 
iododimetacresol ) , Sozoiodol (iodoparaphenolsulphonic acid), etc., in which the 
iodine is combined directly with the benzol ring, do not liberate iodine in the 
organism and consequently act only as aromatic disinfectants. On the other hand, 
similar pyrrol derivatives, such as Iodol (tetraiodopyrrol) , do liberate iodine, 
Recently lsoform (paraiodoanisol) , has appeared to be of value. Of the benzol 
derivatives in which iodine is present in a side chain, Aristol (dithymoldiiodide) 
and Europhen (diisobutylorthocresoliodide) may be mentioned. 

Bismuth preparations, such as Xeroform (tribromphenol-bismuth) and Airol 
(bismuth-oxyiodogallate), and formaldehyde compounds, are also employed for 
the same purpose as iodoform. 

BIBLIOGRAPHY 
Baumgarten: Berl. klin. Woch., 1887, No. 20. 
Behring: Deut. med. Woch., 18S7, No. 20; 1888, p. 653. 
Heile: Arch. f. klin. Chirurgie, 1903, vol. 71, p. 781. 
Loeb, Oswald: Arch. f. exp. Path. u. Pharm., 1907, vol. 56. 
Troje u. Panke: Berl. klin. Woch., 1891, No. 20. 

URINARY ANTISEPTICS 
The drugs which are excreted in the urine in an antiseptically 
active form are discussed in another section (see p. 367). 

INTESTINAL DISINFECTION 
Any real disinfection of the intestines is impossible of attain- 
ment, and in fact it is doubtful whether it is possible by pharma- 
cological agents to cause even an inhibition of the growth of the 
intestinal flora. It must be remembered in this connection, however, 
that great difficulty attends the demonstration of any diminution 
of the growth or of the activity of intestinal bacteria (Stern). 

Often the quantity of the conjugated aromatic substances of the urine which 
are formed by proteid decomposition in the intestine has been used as a measure 
of the amount of bacterial fermentation in the intestine; but, in addition to the 
fact that this factor permits an estimation only of the intensity of proteid putre- 
faction, and not of 'the activity of other bacteria, — for example, those fermenting 
carbohydrates, — the quantity of these aromatic substances excreted in the urine 
depends also upon the extent to which they are absorbed, as also on the extent 
to which they are further transformed in the organism. It is, therefore, clear 
that this method of estimating the bacterial activity in the intestine must be 
very unreliable. The attempt has also been made to determine the effects of 
supposed intestinal disinfectants by determining the number of bacteria in the 
faces before and after the administration of such drugs, as also by determining 
the viability of non-pathogenic foreign bacteria after their passage through the 
intestine. These methods also permit conclusions only as to the life conditions 
for the bacteria in the lowest segments of the intestines, while the particularly 
important thing in intestinal disinfection is the influencing of bacteria in the 
small intestine. For these various reasons, those experiments in which the bac- 
teria were counted in material obtained from the small intestine through fistulse 
have given the most reliable information. [Even such investigations have indi- 
cated that few, or none, of the so-called intestinal antiseptics exert any appre- 
ciable effect on the intestinal flora. The composition of the diet appears to be 
one of the most important factors in determining the nature or types of the 
strains predominating in the intestine. — Tr.] 

Only those substances can act as intestinal disinfectants which 
are not absorbed completely in the upper portion of the intestine 



ANTHELMINTICS 521 

and which, on account of their difficult absorption, are relatively 
non-toxic. One of the most widely used intestinal antiseptics is 
salol, or phenyl salicylate, which is rather insoluble and is decomposed 
in the intestine into its two antiseptic components, phenol and 
salicylic acid. Salicylic acid itself, as also napthaline, beta napthol, 
and particularly thymol, have been stated to exert more or less dis- 
infectant action in the intestine. The most efficient intestinal disin- 
fectant, however, is calomel, which probably owes its efficiency more 
to its cathartic action than to the fact that it is partially transformed 
into soluble mercury compounds which possess antiseptic powers. 
[This is very doubtful. See Harris. — Tr.] 

BIBLIOGRAPHY 

Harris: J. of A. M. A.. 1912. 

Stern: Ztschr. f. Hygiene u. Infekt., 1S92, vol. 12, p. 88. 

ANTHELMINTICS 

Anthelmintics, or vermifuges, are drugs used to expel intestinal 
animal parasites, such as the various tapeworms, Taenia solium, T. 
medioeanellata, Bothriocephalus latus, round worms or Ascaris 
lumbricoides, Oxyuris vermicularis, and the hook-worm, Ankylostoma 
duodenal or Uncinaria amerieana. They are all substances the value 
of which has been discovered empirically, and which possess the 
property of reaching the lower portion of the intestine without being 
absorbed to any great extent. Their toxic action is by no means 
specific, for, being absorbed with difficulty, they come in contact 
with the parasites in the intestines in much .jtronger concentrations 
than reach the tissue cells of the host when they are absorbed. If 
they are absorbed in large amounts, they are all toxic in the host 
also. 

These anthelmintics do not always kill the parasites, but only 
benumb them, so that the Avorms are no longer able to hold fast 
to the mucous membrane by their suckers, and consequently may 
be readily evacuated with the general intestinal contents. For this 
reason, in case the vermifuge itself does not produce catharsis, a 
cathartic should be administered some time after the vermifuge, in 
order that both the parasites and the unabsorbed portion of the toxic 
drug may be expelled from the intestine. 

A a preliminary preparation in the treatment, it is advantageous to empty 
the intestine by a mildly acting laxative in order that the action of the drug on 
the parasite will not be interfered with by tlie presence of too large amounts of 
material in the intestine. However, it is a mistake to empty the intestine com- 
pletely by too long-continued preliminary fasting or purging, for this increases 
the danger oi the absorption of the vermifuge and consequently augments the 
danger of poisoning. 

Oleobesina asipimi, obtained from the rhizome of filix-mas, or 
male fern, is a dark green thick oil, with a very disagreeable taste. 



522 ETIOTROPIC PHARMACOLOGICAL AGENTS 

which contains a number of active principles which have been 
isolated in pure form only comparatively recently (Poulsson, Bohm). 

These are non-nitrogenous acids, of which the most important is filicic 
acid, or filicin, which in crystalline form is inactive but occurs in the fresh 
oleoresin in an amorphous active form. 

Other active principles are flavaspidic acid, albaspidin, and aspidinol, etc., 
and also an amorphous substance named filmaron ( Kraft ) . In other ferns 
very similar substances occur, which, like those named above, are all compounds 
of butyric or isobutyric acid with phloroglucin and its homologues. 

These active principles are both neurotoxic and myotoxic poisons. 
In invertebrates Straub has found that filicic acid is very toxic to 
smooth muscle, and it is probable that the medicinal activity of male 
fern is dependent on its power of paralyzing the muscles of the 
different taenia. 

In mammals filicic acid causes excitation of the central nervous 
system, evidenced by twitching of the muscles and often by tetanic 
convulsions, and finally it causes paralysis of the muscles, heart- 
failure, and collapse. In man also poisoning has often been observed 
after too large doses or improper administration of this drug. Under 
these conditions the first symptoms are due to gastro-intestinal irrita- 
tion, which causes nausea, vomiting, and purging, later stupor and 
faintness or even convulsions may develop, while cardiac weakness, 
disturbances of respiration, and temporary impairment of the vision, 
or even permanent blindness due to optic atrophy, may also result 
from its administration. Most of the cases of poisoning recorded have 
been the result of exceeding the admissible dose (see below), which at 
the highest should not be larger than 8-10 gm. of the oleoresin, or have 
resulted from the repetition of an unsuccessful treatment on the follow- 
ing day. [Many American authors unite in recommending that the 
maximum dose should not exceed 6.0 gm. — Tr.] 

In the usual doses, not exceeding 8.0 gm., male fern in almost all 
cases is well borne if administered on a not entirely empty stomach 
and if, one or two hours after its administration, calomel, senna, or 
other efficient cathartic be administered, so as to bring about a thorough 
removal of the drug. [Castor oil should not be used as a cathartic in 
these cases, for the literature shows that many of the cases of poisoning 
have been those in which this drug, which is a solvent for the poisonous 
active principles, has been administered. — Tr.] The relative non-tox- 
icidity of filicic acid for the host is due in part to the destruction of this 
drug in the organism of the higher animals (Straub). 

Kousso, or koosso, the dried female flowers of Hagenia abyssinica, 
long used as a tamicide, contains substances which, like the active con- 
stituents of the various ferns, are compounds of butyric acid with 
members of the phloroglucin series, the most important being the 
amorphous koussotoxin (Lobbeck). In the lower animals this too is 
a powerful muscle poison, resembling filicic acid. Prom 15.0 to 25.0 
gm. of the crude drug in the form of a decoction acts as an efficient 



ANTHELMINTICS 523 

vermifuge, usually without causing serious symptoms. However, only 
the fresh blossoms are reliable in their action. 

Kamala, the glands and hairs of the capsules of Mallotus philip- 
pinensis or Kottlera tinctoria, occurs as a granular brick-red powder, 
odorless and nearly tasteless, and in the dosage of 6.0-12.0 gm. is 
employed as a mildly acting vermifuge. As this drug itself exerts 
a cathartic action, it need not be followed by a laxative. Its active 
constituent, the resinous rottlerin, is also a phloroglucin derivative. 

Pelletierixe. — The active constituents of granatum, the bark of 
Punica granatum, and of the betel or areca nut, are all alkaloids. 
Granatum contains, in addition to very considerable amounts of tan- 
nic acid, a number of alkaloids of which pelletierine and isopelletierine 
are very toxic to the various tapeworms. [The pelletierine of com- 
merce is a mixture of various alkaloids. — Tr.] Doses of 0.3-0.4 gm. 
pelletierine sulphate or tannate usually act as efficient tamicides with- 
out causing severe symptoms of poisoning. They are best admin- 
istered together with 0.5-1.0 gm. of tannic acid, in order that the 
alkaloid may be retained in the intestine in the form of its rather 
insoluble tannate. The symptoms of poisoning, when this occurs, 
consist of dizziness, faintness, and weakness, and occasionally serious 
disturbances of vision. The crude drug is of uncertain activity ex- 
cept when fresh, and, as from 50 to 60 gm. must be taken within 
an hour, the large amount of tannic acid contained in it (sometimes 
as much as 22 per cent.) is a great disadvantage in connection with 
its use, as it ma}' cause nausea and vomiting. The tannin can, how- 
ever, be removed from the decoction by treating it with chalk or 
milk of lime. 

<>,, the higher animals pelletierine is a central nervous excitant 
[v. Schroder) and, in addition, exerts an action on the muscles similar to that 
of veratrine. Its relatively great toxicity on tapeworms is probably dependent 
on this action on the muscles. 

Betel or area nuts are used, particularly in veterinary practice, as tseni- 
cides. Arecolin, the alkaloid contained in them, belongs, according to its pharma- 
cological actions, in the muscarine and pilocarpine group (see pp. 153 and 372). 
On account of the readiness with which it is absorbed, this drug is too dangerous 
to be used as a ta-nicide. 

Santonin, the active principle of santonica, or levant wormseed, 
which is the only drug used to expel the round worm, Ascaris lumbri- 
coides, is an acid anhydride. According to v. Schroder, santonin does 
not kill these worms, but only drives them down into the large in- 
testine, from which they may be readily removed by a cathartic, 
it is absorbed with extreme difficulty, ;m<l is consequently to a large 
extent excreted in the i',-e<vs, but a, certain portion may be absorbed 
and cause poisoning. 

Pharmacologically it is a convulsant, which in animals causes 
epileptiform convulsions, marked depression of the temperature, and 
dentil. In man also its use has been observed to cause not only 



524 ETIOTROPIC PHARMACOLOGICAL AGENTS 

nausea, vomiting, and purging, but also convulsions. It frequently, 
even in moderate doses, causes a very marked effect on the vision, as 
a result of which objects appear to be first violet in color and later 
yellow. This effect is known as xanthopsia. Disturbances of the 
senses of smell and taste may also occur. The urine contains a trans- 
formation product of santonin, santogenin (Jaffc), which in alkaline 
reaction colors the urine cherry-red. The dose of santonin ranges 
from 0.02 gm. up to the maximum dose of 0.1 gm. [Forcheimer states 
that he has seen death follow a dose of santonin in a child to whom it 
had been given on a suspicion of the presence of worms, although in 
reality this was not the case. He also states that 0.13 gm. has caused 
death in a child. — Tr.] 

Thymol. — In the treatment of hook-worms, thymol is the drug 
par excellence. This occurs as large colorless crystals possessing an 
aromatic odor and pungent taste. [It is soluble in 1200 parts of 
water and in one part of alcohol, and fairly soluble in fats and oils 
and in alkaline solutions. Extensive experience in the treatment of 
this disease has shown thymol to be, when properly administered, a 
very certain means of causing the expulsion of these parasites, and 
that its use is unattended with danger if it be administered with the 
observance of certain simple and necessary precautions. 

The dose should not exceed 4.0 gm., best administered in capsules 
containing about 0.5-0.7 gm. in finely divided form and triturated 
with milk-sugar. These should be taken on an empty stomach, and 
followed in from one to two hours by a promptly acting cathartic, 
preferably magnesium or sodium sulphate. For twelve hours before 
its administration and following its administration until the bowels 
have moved thoroughly, no fatty or oily food, or alcohol, should be 
taken. Stiles states that he has known of fatal results due to the 
administration of castor oil as a purgative following the thymol. — Tr.] 
One death, following the administration of 6 gm. to an anamiic indi- 
vidual, warns against its indiscriminate or careless use. [As a rule, 
only comparatively slight systemic symptoms should occur, and in 
fact with precautions even these occur but seldom. Its toxic action 
closely resembles that of carbolic acid. — Tr.] 

BIBLIOGRAPHY 

Bohm: Arch. f. exp. Path. u. Pharm., 1897, vol. 38, p. 35. 
Bbhm: Annalen der Chemie, 1902, vol. 318, p. 230. 

Forcheimer: Prophylaxis and Treatment of Internal Disease, 2nd ed., p. 186. 
Jaffe: Ztschr. f. physiol. Chemie, 1897, vol. 22. 
Kraft: Arch. d. Pharmacie, 1904. 
Lobbeck: Arch. d. Pharm., 1901, vol. 239. 
Poulsson: Arch. f. exp. Path. u. Pharm., 1891, vol. 29. 
Semper: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 10. 
Straub: Arch. f. exp. Path. u. Tharm., 1902, vol. 48. 

v. Schroder, W.: Arch. f. exp. Path. u. Pharm., 18S4, vol. 18, p. 381 ; 1885, vol. 19, 
p. 304. 



SPECIFIC DISINFECTANTS 525 



SPECIFIC DISINFECTANTS 

The general antiseptics kill the protoplasm of all microbes as also 
that of the tissue cells. However, there are very distinct differences 
in the susceptibility of the different pathogenic and non-pathogenic 
varieties to the different antiseptics. This higher susceptibility of 
certain types forms, as it were, a bridge to the outspoken specific 
relationship between certain pathogenic organisms and certain cell 
poisons, on which depends the possibility of killing such parasites, 
even in the tissues of the host, without harming him. 

"Where such specific relationships do not exist, an internal dis- 
infection is from its very nature impossible. Even in mucous mem- 
branes and wounds, general cell poisons cannot produce disinfection 
without severely damaging the tissue cells, and consequently it is 
absolutely impossible to utilize such general cell poisons as means 
of attacking the micro-organisms in the blood and in the interior of 
the tissues, because, on the one hand, the greater susceptibility of the 
central nervous system from the start prevents the use of higher 
concentrations, while, on the other, even those concentrations which 
are effective on the surface of wounds are not effective in the blood 
and in the tissues, for the disinfectant is diverted from the pathogenic 
organisms by the constituents of the body to a much greater extent 
when it is present in the general circulation than is the case in 
the secretions of wounds. 

A striking example of the disproportion between disinfectant power in the 
reagent glass and in the organism has been furnished by the observations of 
Bechhold and Ehrlich, who discovered in tetrabrom-o-kresol and in hexabrom- 
dioxy-diphenylcarbinol two substances possessing extraordinary disinfecting power 
outside of the body and relatively slight toxicity. It was consequently possible 
to introduce these antiseptics into the bodies of animals in doses less than one- 
one-hundredth part of which would have been sufficient to prevent the further 
development of pathogenic bacteria (diphtheria) if they had been as effective 
in corpore as in vitro. However, these drugs failed entirely to cause an internal 
disinfection. This is explained by the fact that even blood-serum markedly less- 
ened their disinfectant power, and in the body it is evident that the conditions 
were still more unfavorable for the absorption of the disinfectants by the 
bacteria. 

Tli is explains why, except in the case of specific drugs, internal 
disinfection Jails, as does, for example, intravenous injection of cor- 
rosive sublimate which has been tried in various diseases of the lower 
animals. On the other hand, it is easy to understand why the at- 
tempta to obtain an internal disinfection have never been abandoned, 
for the effects of quinine in malaria and of mercury in syphilis cer- 
tainly prove that such specific therapy is a possibility. Particularly 
against tuberculosis, specifics arc constantly being recommended, but. 
unfortunately, only after insufficient investigation. 

Tin: oeeosotb TREATMENT of thbkucttlostk has become of practical 
importance. The tar obtained from hooch wood is one of the 
antiseptics longest known. From it is obtained, by distillation, a 



526 ETIOTROPIC PHARMACOLOGICAL AGENTS 

dark yellow fluid with a smoky odor and burning taste — creosote. 
This is composed chiefly of guaiacol, the methyl ether of brenzcatechin, 
which, in pure form, occurs as colorless crystals, but which, as ob- 
tained in commerce, is usually a fluid differing from creosote chiefly 
in its less disagreeable odor. Guaiacol itself is a powerful antiseptic, 
but whether after absorption it can exert this action or whether it 
circulates in the blood in active combinations has not been definitely 
determined. It is excreted in the urine as an ethereal sulphuric acid. 

In the mouth creosote and guaiacol cause burning and, when taken 
in concentrated solution, violent irritation of the mucous membranes, 
with vomiting and purging. Although guaiacol resembles the related 
phenol in tbese local actions, after absorption it is less toxic. When 
rapidly absorbed, as after subcutaneous administration, it, like other 
aromatic compounds, lowers the temperature [and acts as an an- 
algesic. — Tr.] 

After having been used to a large extent in Prance, creosote was 
introduced into Germany especially by Sommerbrodt in 1887, but was 
soon replaced by the purer and less irritant guaiacol. Numerous 
clinical observers testify to the fact that, when administered for a 
considerable period in increasing doses, up to one gramme per diem, 
it causes improvement of the appetite and nutrition, with gain in 
weight, and also exerts a favorable influence on the cough and 
expectoration. Perhaps a slight — quantitatively hardly measurable 
— amount is excreted through the lungs. 

It appears to be impossible that without causing systemic poisoning 
one can attain a concentration of guaiacol on the blood and tissues 
which will suffice to kill the tubercle bacilli (Guttmann, Cornet) 
and even an inhibition of their growth by such means appears 
improbable, for, like other phenols, guaiacol is rapidly transformed 
in the body into antiseptically inactive conjugated sulphates. In 
case creosote and guaiacol actually do exert favorable actions in 
tuberculosis, these must be attributed to their indirect actions, per- 
haps because, like bitters, these drugs favorably affect the digestion 
and possibly also act as intestinal antiseptics. From this point of view 
it appears rational to attempt only a mild treatment with these 
drugs, and not the so-called intensive treatment, in which, by combin- 
ing with their internal administration their administration through 
the skin and as inhalations, the endeavor is made to attain the highest 
possible saturation of the organism with guaiacol. Moreover, it 
should be remembered that the oral administration of large doses 
quite often causes disturbances of the digestion. 

It is for this reason that at present the preference is given to the 
carbonates of creosote and guaiacol (creosotal and duotal), which are 
insoluble and consequently non-irritant in the stomach, but which 
are decomposed gradually in the intestine. Of similar preparations 
mention may be made of the valerianate of creosote (Eosot) and of 



QUININE IN MALARIA 527 

guaiacol (Geosot), potassium guaiacol sulphanate (Thiokol), a powder, 
of which the dose is from 2 to 5 gm. daily, and its solution, Sirolin. 

BIBLIOGRAPHY 

Bechhold u. Ehrlich: Ztschr. f. physiol. Chemie, 190G, vol. 47. 
Cornet: NothnagePs Handbucb d. Path. u. Ther., vol. li, p. 536. 

Guttmann: Ztschr. f. klin. Med., 1888, vol. 13. 

In various protozoal diseases it has been definitely shown that 
drugs may produce specific etiotropic actions, for quinine kills 
malarial parasites and certain arsenical compounds can kill try- 
panosomes and the Spirochteta pallida. The action of mercury in 
syphilis is another example of such specificity, and it is in the 
highest degree probable that salicylic acid also is an etiotropic cura- 
tive agent, acting on the still unknown cause of articular rheumatism. 

QUININE IN MALARIA 

Through its action on heat regulation and metabolism, quinine is 
an antipyretic, which more or less efficiently controls pyrexia in 
various infectious diseases. Its almost universally curative effect 
in malaria is, however, due to altogether different causes, for here 
all the symptoms of the disease and not the fever alone are controlled 
by it. Here we are dealing with a typical example of specific etio- 
trophic therapy, for in doses which are harmless to man quinine 
damages and destroys most of the forms of the malarial parasites 
in the blood. 

Up to the eighth decade of the last century it was generally as- 
sumed that in malaria quinine produced its effects through its action 
on the nervous system, but in 1867 Binz demonstrated the great 
susceptibility to this drug exhibited by certain simple protoplasmic 
organisms, and based on this the hypothesis that quinine cured 
malaria by acting directly on its cause, which probably would be 
found to be one of the lowest forms of living organisms. He further 
stated that quinine was much less toxic to the healthy cells of man 
than to this hypothetical cause of malaria. 

The first objects used by Binz in these investigations -were paramecin, 
Which were immediately killed by a one to four hundred solution, and whose 
movements were lessened by solutions of one to twenty thousand and entirely 
stopped after two hours, although these same infusoria were much more resistant 
(. i other alkaloids, such as morphine, strychnine, santonin, etc. Bmz was able 
t.> demonstrate the same striking susceptibility to quinine in fresh-water amcebia, 
and als,, in the leucocytes Of the blood, which in dilutions of one to fifty thousand 

cease their amoeboid movements and undergo gross granular degeneration. On 

the other hand, other amrriiia — for example, -alt water euglena — arc much more 

resistant. Quinine is also a very powerful poison for various bacteria. From 
these various facts, Binz was justified in concluding that this drug acted as a 
specific. 

The proof of the correctness of this theory of the manner in 
which quinine acted could be obtained only after Lorn run, in 1880, dis- 
covered and recognized the Plasmodium malaria; as the cause of this 



528 ETIOTROPIC PHARMACOLOGICAL AGENTS 

disease, and after this discovery had been confirmed by numerous in- 
vestigators, when it was found that, even outside the body, the ad- 
dition of quinine solutions to the blood rapidly kills the malarial 
organisms. All the investigations of the blood in malaria have shown 
that during the administration of quinine the parasites disappear 
from the blood, and that they may be recognized as persisting there 
only in those pernicious cases which are not cured by quinine. 




Fig. 61. — Tertian malarial parasites: a-e, normal; /, as affected by quinine; 
g, speculation under influence of quinine. 

In malaria the paroxysms of fever are due to the fact that the 
youngest forms of the sporozoa, the so-called sporozoits, which have 
penetrated into the red blood-cells and developed within them, after 
a time sporuiate and leave the old corpuscles and penetrate into 
new ones. As it is in this phase of their life history that quinine is 
most toxic to these parasites, when given some hours before the ex- 
pected paroxysm, it destroys them in large numbers and prevents 
the next paroxysm or moderates its severity in many instances, or at 
least prevents its recurrence. Tertian parasites are most susceptible 
to the toxic action of quinine, the quartan ones somewhat less so, and 
least of all those of the pernicious ajstivo-autumnal fever, which sporu- 
iate almost entirely in the internal organs. It is stated that quinine 
is without effect on the gametes of the severer forms of malaria whose 
sexual cycle occurs only in anopheline mosquitoes. [This, however, 
is not true, for, although very resistant to quinine, the persistent ad- 
ministration of large doses of quinine causes the disappearance of these 
parasites from the blood, at any rate for a time, or at the least causes 
a marked diminution in their number (see van Bezdorf). — Tr.] 

Quinine muriate is usually administered in tertian and quartan 
malaria, three to five hours before the expected paroxysm, in doses of 
0.3 to 0.7 gm., repeated two to three times at hourly intervals, and its 
daily administration in somewhat smaller doses should be continued 
for a considerable period after the disappearance of active malarial 
manifestations. In severe cases it is administered several times 
daily in doses of 0.6-1.0 gm. [In refractory or pernicious cases it 
should be injected intramuscularly, for which purpose the very solu- 



SALICYLIC ACID IN RHEUMATISM 529 

ble bimuriate or the muriate of quinine and urea are the most suitable 
preparations. — Tr.] It has also been recommended that quinine should 
be given in broken doses, 0.2 gm. repeated five times daily, with the idea 
that in this fashion a regular and continuous absorption will occur; 
and that a persisting action in the blood will result. 

Quinine is slowly absorbed and at least in part remains in the 
blood in an unaltered form, for one-fourth to one-third of the amount 
administered in 2-i hours is excreted unchanged in the urine {Giemsa 
u. Schaumann, Nishi) . The remainder is destroyed in the organism. 
Its relatively slow excretion renders it possible to attain with permis- 
sible doses a constant concentration of quinine in the blood, which 
endows the taker with a certain amount of prophylactic protection 
against the sporozoits which may be introduced by mosquitoes. In 
addition to the symptoms of cinchonism already mentioned (p. 477), 
large doses at times cause hematuria or hemoglobinuria, and it is 
probable that, particularly in patients severely ill with malaria, 
quinine causes the so-called black-water fever. [The evidence for and 
against quinine as a frequent cause of hemoglobinuria is very con- 
flicting, but it is reasonably certain that, while quinine is not respon- 
sible for all black-water fever occurring in malarial patients, it is often 
the final decisive factor in its production. This, however, does not 
constitute a contraindication for its administration in any cases of 
malaria, not even in cases with black-water fever, so long as the para- 
sites may be found in the blood. — Tr,] 

BIBLIOGRAPHY 

Binz: Zbl. f. med. Wiss., 1867, p. 310. 

Binz: Arch. f. mikrosk. Anat., 1867, vol. 3, p. 383. 

Giesma u. Schaumann : Arch. f. Schiffs- unci Tropenhvg., 1907, vol. 11. 

Nishi: Arch. f. exp. Path. u. Pharm., 1909, vol. 60, p. 312. 

van Bezdorf: Southern Med. Jour., 1913. 

SALICYLIC ACID IX ACUTE ARTICULAR RHEUMATISM 
In all probability the action of salicylic acid in this disease is of an 
etiotropic nature, although this cannot be certainly maintained inas- 
much as the pathogenic organism is not known. Probably the causative 
agent closely resembles streptococci and staphylococci, and, therefore, 
it probably is not of protozoal nature. Consequently, this drug may 
be looked upon as one of the group of general bacterial poisons which 
possesses specific curative properties. As these bacterial poisons are 
at the same time general cell poisons, and as salicylic acid is by no means 
xrry much more toxic to bacteria in general than it is to the suscep- 
tible tissues of the host, its utility as an internal disinfectant must 
depend on certain special conditions, as a result of which its toxic 

action on tie- central nervous system may be avoided while it may still 

be directed against the causative agent of rheumatism. 

Free salcylic acid is scarcely less toxic to bacteria than is phenol, 
while it ig a1 the same time strongly toxic to the tissues. On the other 

34 



530 ETIOTROPIC PHARMACOLOGICAL AGENTS 

hand, the salicylate of soda is a very feeble antiseptic and at the same 
time very slightly toxic to the tissues. As salicylic acid circulates 
in the blood chiefly or entirely in the form of its sodium salt, it is evi- 
dent that after absorption it circulates about in a form which is but 
slightly toxic for the patient's tissues but at the same time also but 
slightly toxic for the bacteria. However, as shown by Binz, a rather 
high carbon dioxide tension sets free the active acid from the salicy- 
lates. "While the C0 2 tension of normal tissues (about 6 per cent.) is 
not sufficient to do this, that of inflamed tissues, which may rise to 
17.5 per cent. (Eivald), is amply sufficient. Even in the blood of 
asphyxia, containing about 12 per cent. C0 2 , appreciable amounts of 
salicylic acid can be set free from its salts, and consequently it is pos- 
sible that in inflamed joints a local antiseptic action may be exerted 
although the salicylate never reaches a harmful concentration in the 
other tissues, especially the nervous system. 

After absorption salicylic acid is retained in the blood in strikingly 
large amounts and for a long time (Jacoby u. Bondi), and, while 
the bones contain very little, the muscles and particularly the joints 
contain much more. These findings also help to explain the fact that 
the action of this drug is to a considerable extent limited to the joints. 
These authors also found that in the joints of rabbits infected with 
staphylococcus aureus much larger amounts of salicylic acid were 
present than in those of the controls. These results indicate that this 
drug is especially attracted to and retained by the bacteria localized 
in the joints or by the substances produced by them in the inflamed 
tissue. Perhaps under these conditions the higher C0 2 tension plays a 
role in liberating salicylic acid, which on account of its solubility in 
lipoids penetrates into the cells and remains in them. 

Therapeutic Employment. — In acute articular rheumatism 
sodium salicylate is administered in doses of 3.0-5.0 gr. per diem and 
in severe cases at the start in doses of 6.0-10.0 gr., which are reduced 
later. While as a result of its administration not only the fever but 
also the pain and swelling of the joints disappear, all too frequently 
such doses cause disagreeable side actions, resulting in the development 
of salicylism. On account of its irritating properties, free salicylic 
acid is no longer used internally. Inasmuch as the free acid is liberated 
from the salicylates by the gastric HC1, their administration may also 
cause symptoms of gastric irritation, which are only slightly lessened 
[ ? Tr.] by administering sodium bicarbonate with them. The neutral 
esters of salicylic acid which are decomposed only when acted upon by 
the intestinal ferments, however, do not irritate the gastric mucosa. 
This is the reason for one important superiority of phenyl salicylate, or 
salol, and of acetyl salicylate, or aspirin, and of other similar salicylic 
acid compounds. 

Undesirable Effects. — In addition to gastric disturbances, buzzing 
in the ears is the most common undesirable effect of the salicvlates. 



ACTION OF ARSENICAL COMPOUNDS 531 

Albuminuria and cylindruria are also caused, even by therapeutic 
doses of the salicylate of soda, but the evidences of renal irritation 
disappear after discontinuance of its administration (Lilthje). In 
pronounced salicylism, vomiting, excitement, vertigo, disturbances of 
vision, delirium, and even dyspnoea (Quincke) may occur, and very 
large doses may cause alarming slowing of the pulse and respiration 
with collapse and cardiac failure. 

In mild poisoning it is sufficient to discontinue the drug, while in 
pronounced poisoning Ehrmann states that the administration of large 
doses of sodium bicarbonate may aid in causing the more rapid elimina- 
tion of the salicylates. 

These disagreeable systemic actions of the salicylates are due to 
too large amounts being absorbed at one time. After the adminis- 
tration of the rather insoluble esters, such as salol, the absorption 
occurs very gradually, for these preparations may reach even the 
lower portions of the intestines unaltered, — after very large doses 
salol appears in the faeces, — salicylic acid being liberated from them 
only gradually. As a consequence, after their administration salicylic 
acid is distributed throughout the body in a constant but low concen- 
tration. For this reason the curative effect of their administration 
is less striking and is produced more slowly. 

Solol is usually administered in doses of 1.0 gm. five to six times 
a day. In the same fashion, when acetyl-salicylic acid (aspirin), 
acetyl paramidophenol (salophen), or salicylic acid, salicylic ether, 
(diplosal) is administered, it is easier to avoid the buzzing in the ears 
and the other undesirable side actions. Methyl salicylates and other 
fluid salicylic esters are applied locally to the skin, through which their 
absorption readily takes place. 

BIBLIOGRAPHY 

Binz: Berl. klin. Woch.. 1870. No. 27. 

Binz: Arch. f. exp. Path. u. Pharm., 1870, vol. 10, p. 147. 

Ehrmann: Miinch. med. Woch. s 1907, No. 52. 

Ewald: Dubois' Arch., 1870, p. 422. 

Jacobi und Bondi: Hofmeister'a Beitr. z. physiol. Chemie, 1900, vol. 7, p. 514. 

Lilthje: Deut. Arch. f. klin. Med.. 1902, vol. 74. 

Quincke: Berl. klin. Woch., 1907, No. 52. 

ACTION OF THE ARSENICAL COMPOUNDS ON PROTOZOA 
The etiotropic action of quinine in malaria has shown that, in those 
pathogenic organisms which belong to the class of protozoa, the sus- 
ccplibility toward specific poisons can be greater than that of the cells 
of the higher organisms, and that consequently such specific antiseptics 
may produce an internal disinfection without working injury to the 

host. 

AUSKNIC IN TRYPANOSOMA IHSEASES 

Particularly useful in enlarging our knowledge of the specific 
etiotropic relations of this class of pathogenic organisms has been the 



532 ETIOTROPIC PHARMACOLOGICAL AGENTS 

study of the experimental chemotherapy of the various trypanosome 
diseases. The causative agents of these diseases, to which the African 
sleeping sickness and numerous animal and human diseases of the 
tropics belong-, may be readily and successfully inoculated into labora- 
tory animals such as mice, so that trypanosomes in large numbers 
appear in their blood. In 1902 Laveran and Mesnil found that these 
organisms disappeared from the blood after the subcutaneous injec- 
tion of .01 mg. of arsenic trioxide, and that mice, which otherwise 
would have succumbed to the infection inside of three or four days, 
continued to live for some time longer. Although after a time the 
parasites reappear in the blood, they may again be caused to disappear 
by repeating the administration of arsenic, but, unfortunately, the 
mice finally succumb to the repeated administration of this drug, 
the curative agent being, in comparison with its efficiency against the 
pathogenic organisms, too toxic for the host. 

Organic Arsenic Compounds. — The further development of etio- 
tropic arsenic therapy, which has, as its last achievement, led to 
Ehrlich's discovery of a new cure for syphilis, is built up upon the 
study of the manner in which complex metallic compounds act in the 
body. As has been previously explained, organic * metallic com- 
pounds, including those of arsenic, which do not contain the toxic 
element in an ionizable form, do not exert the direct toxic actions 
of their metallic constituents. For example, potassium ferrocyanide, 
whose solutions contain potassium ions and FeCy ions but not Fe and 
Cy ions, does not exert the direct toxic actions either of iron or of the 
cyanides, for in this complex compound they are not able to act as 
such, as they are present in it only in a masked form. So long as such 
complex compounds are not broken up in the body, they produce 
only their own peculiar pharmacological effects, but, when they are 
broken up so that the metallic ions are liberated, the effects of these 
latter are produced. 

The ferrocyanide of potash is consequently very slightly toxic and, 
as it passes through the body unchanged, after its administration no 
secondary effects from its decomposition products may be observed. 
If, on the other hand, such complex compounds are decomposed in the 
body, the toxic action of metallic ions is sooner or later exerted, but, 
as a rule, they are exerted in different locations and with different 
intensity than when the simple ionizable compounds are administered. 
It is just this peculiar property of the complex organic metallic com- 
pounds which is decisive for their pharmacological value. 

The points at which the organic compounds act and, at the same 
time, the nature of their effects and the order in which they appear 
depend on the physicochemical properties of the substances in ques- 

* In this section, by organic compounds are meant such compounds as 
contain the metal firmly attached to carbon and consequently in non-ionizable 
form. 



ACTION OF ARSENICAL COMPOUNDS 533 

tion, these determining whether the complex compounds can penetrate 
into various organs and cells of the body, to which the simple ionizable 
metallic compounds penetrate either not at all or only in the course 
of very chronic poisoning, in which latter case they probably must 
first be changed within the body into very complex compounds. Not 
only the quantitative but also the qualitative differences observed 
between acute and chronic metallic poisoning are based on such con- 
siderations. 

For example, in acute lead poisoning in man the symptoms consist 
essentially of those of gastro-enteritis and somewhat later of colic, 
while only after poisoning lasting weeks and months do the well-known 
lesions of the nervous and muscular systems develop. The same is 
true of experimental poisoning with simple lead salts. If, however, 
as in Harnack's experiments, an organic complex lead compound, like 
the triethylate of lead, be used to poison the animals, the result is 
very different, for, on account of its physicochemical properties, this 
substance very quickly penetrates into nerve and muscle cells and, 
after a rapidly passing peculiar molecular action, soon produces the 
same nervous and muscular lesions as are seen in chronic lead poison- 
ing. It is thus evident that this complex compound has made it pos- 
sible for the lead ions, which are contained in it and which later are 
liberated from it, to be distributed about in the body very differently 
from those ions which are contained in the simple inorganic lead salts. 

In a similar fashion the diethylate of mercury, Hg(C,H5),, being a very 
stable compound, causes at first only very marked and characteristic toxic actions 
on the central nervous system, while the usual effects of mercury appear only 
very much later (llepp). 

The same holds good for the organic arsenic compounds, which, in 
accordance with their particular distribution in the organism, act on 
the tissues in situations which the ordinary arsenic compounds do not 
reach at all. It is this which is decisive for their value as drugs which 
will exert more or less elective toxie actions on pathogenic organisms. 

Of these organic arsenic compounds, cacodylic acid has been widely 
used for therapeutic purposes, — for example, in phthisis, — while, since 
its recommendation by Gautier in 1896, it, as well as other organic 
arsenic compounds, has been used in the treatment of syphilis. Caco- 
dylic acid, however, is broken up with too great difficulty, and conse- 
quently is not well adapted for the production of the etiotropic actions 
of arsenic. 

Consequently, the stimulus was given for a search for organic 
arseniciil compounds, which were sufficiently non-toxic and which could 
he absorbed and carried about in the organism in unaltered form, so 
that they mighl penetrate into the parasites, in which I hey mighl in 
some manner or other, probably in the parasites themselves, be trans- 
formed into products toxic for these parasites. The greatesl value as 
etiotropic agents must, be possessed by such organic compounds as arc 



534 ETIOTROPIC PHARMACOLOGICAL AGENTS 

but slightly absorbed or transformed by the cells of the host, but which 
either penetrate more readily into the pathogenic parasites or are more 
readily transformed by them into toxic substances. 

Atoxyl. — Numerous experiments with etiotropic arsenic therapy 
were first conducted with arsenilic acid, or atoxyl, which was intro- 
duced into therapeutics by Blumenthal in 1902. First used in try- 
panosome diseases by Thomas in 1905, the value of this drug was 
proven by Robert Koch in his extensive experiments in treating the 
sleeping sickness. While atoxyl is in large part unaltered in the body 
and circulates about in the blood for a long time, enough of it is 
absorbed and transformed by the cells (Igersheimer u. Rothmann) to 
produce distinct effects. A certain proportion, varying with the 
species of animal used, is excreted unchanged in the urine (Muto), 
while the remainder is transformed in the body into powerfully toxic 
substances. 

With the fixing of atoxyl or of its transformation products in the 
organs is combined the development of specific pharmacological 
actions, which are not produced by the inorganic arsenic compounds. 
Thus, in cats it causes disturbances of the central nervous system 
resulting in ataxia, spasms, and paresis, and, in dogs, renal hemor- 
rhages and lesions in other internal organs (Igersheimer). In accord- 
ance with these actions, after administration of atoxyl, arsenic is found 
in the cat chiefly in the central nervous system, but in the dog chiefly 
in the internal organs (Igersheimer u. Rothmann). 

In agreement with these experimental results, in man atoxyl all 
too frequently causes severe toxic effects, consisting in disturbances of 
the digestive system and nephritis, and in particular in toxic effects 
on the nervous system and on the eyes, as a result of which unpre- 
ventable progressive impairment of vision and permanent blindness 
due to optic atrophy may result from the use of atoxyl. For this 
reason it is of interest that arsenic may be found in the eyes of 
animals poisoned by atoxyl, but not in those of animals which have 
been poisoned by inorganic arsenic compounds and in which optic 
atrophy has not yet been observed (Igersheimer u. Rothmann) * These 
actions of atoxyl are probably to be attributed to its transformation 
products. Similar effects result from the administration of other sub- 
stances closely related to it, such, for example, as acetyl-arsenilic acid. 
The maximum dose of atoxyl per dose and per diem is- .02 gm. 

Atoxyl when continuously administered must also in part be transformed 
into some inorganic arsenic compound or compounds, as, following its adminis- 
tration, symptoms of conjunctivitis, rhinitis, trophic disturbances of the skin, 
etc., occur, all symptoms which are characteristic of arsenic poisoning. 

Atoxyl Derivatives. — Atoxyl has been shown by Ehrlich and 
Bertheim to be sodium paraminophenyl arsonate or arsanilate. This 

♦Seepage 537. 



ARSENICAL COMPOUNDS LN TRYPANOSOMIASIS 535 

has served Ehrlich as a starting-point for extensive experimentation 
•with a very large number of related compounds, which he obtained 
from atoxyl by changing its molecule — by reduction to compounds of 
trivalent arsenic and by the introduction of different side chains. As 
a test object for the curative value of these compounds in protozoal 
infections, animals infected •with trypanosornes have been used. 

The comparison of the efficiency of such substances has disclosed 
certain relationships between their constitution and the degree of their 
etiotropic actions (Ehrlich). Thus, arsacetin, obtained by the intro- 
dution of an acetyl radical into the amido group of atoxyl, was found 
by him to be more efficient than atoxyl. The maximal dose- of this 
drug is the same as that of atoxyl (0.2 gm. per dose and per diem). 

Neither arsenilic acid nor arsacetin kills trypanosornes in vitro, 
although arsenious acid and such organic arsenic compounds as contain 
trivalent arsenic do so, and it has been established that compounds 
containing pentavalent arsenic do not produce a direct effect on 
trypanosornes. 

This is in agreement with earlier experience with arsenic compounds, for 
arsenic pentoxide is far less toxic to animal and vegetable organisms than arsenic 
trioxide, so that it has been assumed that the pentoxide as such is non-toxic and 
becomes toxic only after it is transformed into the trivalent ion (Husemann, 
Loew). The behavior of the trioxide and pentoxide of antimony is quite 
analogous. 



Atoxyl and arsacetin are both compounds containing pentavalent 
arsenic, and it is probable that the curative action of atoxyl and of 



n 



O = As (-OH 
\OH 



/OH 

As ^-CH 3 

\CH 3 



= As 



/OH 

Arsenic acid Cacodylic acid Phenylarsenic acid 

NH 2 NH • (CO CH 3 



= As 






ONa 



O =As 



\:i 




Atoxyl, sodium Arsacetin 

araanilate 

other organic pentavalent arsenic compounds depends on their trans- 
formation into compounds in which the arsenic is trivalent and which 
are directly toxic to protozoa (Bohl, Friedberger), just as arsenic 
pentoxide, according to I*inz and Schultze, is in part reduced in the 
organism to arsenous acid. In para-aininophenylarsenous oxide, Ehr- 



536 ETIOTROPIC PHARMACOLOGICAL AGENTS 

lich has prepared from atoxyl a reduction product which is directly 
toxic to trypanosoms and immediately toxic in the same manner 
as arsenous acid, while even large amounts of atoxyl when injected 
intravenously never produce toxic effects immediately but only after 
a rather long period of latency. 





COONa 


COONa 






CH 2 


CH 2 
NH 




NH 2 

n 


NH 
/\ 

1 | 


OH OH 
NH 2 fN f|NH, 


u 

As = O 

p-Aminophenyl- 
arsenoxyd 


As = As 

Arsenophenylglycin 


w 

As = As 

■Dioxydiamidoarsenobenzol 



Although from the above facts it appears that all compounds of 
trivalent arsenic are much more toxic for the higher organisms than 
are those of pentavalent arsenic, it is possible, by introducing side 
chains into organic compounds of trivalent arsenic, to diminish their 
toxicity to such a degree that they are better borne by the experi- 
mental animals and still remain directly toxic to the protozoa. Thus 
Ehrlich and Bohl were able to cure even severe experimental trypano- 
somiasis by a single injection of arsenophenylglycin in dosage which 
was not dangerous for the host. 

Other Specific Trypanosome Poisons. — Antimonial compounds, like 
those of arsenic, have also proven to be specific etiotropic remedies in 
trypanosomiasis. Moreover, at a period antedating the discovery of 
the arsenic therapy of these conditions, Ehrlich and Shiga discovered 
in trypan red, a dye of the benzopurpurine series, a drug which is 
very efficient against protozoa, and since then it has been found that 
parafuchsin and tryparosan, derivatives of rosaniline, even when 
introduced into the stomach, can cure experimental trypanosomiasis 
{Bohl, Marks). 

If the trypanosomes reappear in the blood of the experimental animals 
after the curative effect of the organic arsenic preparations has passed off, by 
repetition of the injection they may be caused to disappear again, but only to 
return once more. Such parasites, from animals which have been repeatedly 
injected, when reinoculated into other mice, show themselves resistant to this 
remedy when it is administered to these new hosts.* Strains of parasites which 
have thus become resistant to arsenilic acid also show an increased resistance to 
other arsenic and antimony compounds, but not to the specifically toxic substances 
of the benzopurpurine and fuchsin series (Ehrlich). 

ARSENIC IN SYPHILIS. 
The Spirocha?ta pallida, the pathogenic organism of syphilis, dis- 
covered by Schauclinn and Hoffmann, is also a protozoal organism. 

* Concerning similar augmentation of the resistance in infusoria see N0U- 
haus, Arch, intern, de Pharmacodynamie et de Therapie, 1910, vol. 20, p. 393. 



ARSENIC IN SYPHILIS 537 

The close biological relationship, which, according to Schauddnn's 
views, exists between trypanosomes and spirochetes, suggested 
the employment of organic arsenical compounds as etiotropic reme- 
dies in syphilis.* The first clinical curative results were obtained 
by the use of large doses of atoxyl (Salmon, 1907, Lassar, and others). 
Uhlenhut and his collaborators succeeded in experimentally demon- 
strating the efficiency of atoxyl in another spirochetal disease, the 
spirillosis of chickens, and soon after they were able to demonstrate the 
same for experimental syphilis. However, it appears that, in com- 
parison with its toxicity for the patient, the specific etiotropic action 
of atoxyl on the Spirocha?ta pallida is too weak, for in human syphilis 
only large and dangerously toxic doses are effective. 

Salvarsan. — Ehrlich attributes the much more powerful thera- 
peutic action of salvarsan, dioxydiaminoarsenobenzol, to the radical 
containing the trivalent arsenic, the importance of which was rendered 
apparent in experiments with trypanosomes, and also to the introduc- 
tion of hydroxyl radicals in the para position in the molecules, in 
which the amido radicals are in the ortho position relatively to the 
hydroxyl radicals (see formula, p. 536). 

Hal a was able to produce pronounced protective and curative results in 
numerous spirilloses with this preparation, as also with other arsenophenol 
compounds containing hydroxyl groups in the para position. Salvarsan rapidly 
caused tlie spirilla of relapsing fever to disappear from the blood, and has shown 
itself a very powerful etiotropic agent in the spirillosis of chickens, in which 
disease the efficient curative dose was only 1/58 part of the largest non-lethal 
dose, while with atoxyl the curative dose was y 2 of the lethal dose. In rabbits 
it was possible, by the subcutaneous injection of 1/7 to 1/10 of the largest 
non-lethal dose, to cause the spirillar to disappear from the primary lesion in the 
scrotum as early as on the following day (Hata, Tomascsewski) . 

With salvarsan the ratio between the etiotropic efficiency and the 
toxicity is far more favorable than in all the other organic arsenic 
compounds thus far tested, and is particularly far more favorable than 
with atoxyl. This lias thus far been confirmed by clinical experience 
in man, and in particular salvarsan does not produce the same toxic 
effects iii the eye as does atoxyl (Igersheimer) .t In animal experi- 
ments also it does not produce the symptoms characteristic of atoxyl 
and related compounds (Jgersheimer). 

This author was able, ttfter salvarsan had been injected, to recognize the 

presence of arsenic in the syphilitically infected cornea of rabbits, hut not in other 
portions of the eye or in normal eyes, a finding which indicates that the efficient 
arsenical compounds combine with the syphilitic tissues or with the spirochetes 

or their reaction products which may he present in such tissues. 

In man the hydrochloride of dioxycUajninoarsenobenzol, or salvar- 
san. is injected Bubcutaneously and intramuscularly either in alkaline 
solutions or in neutral suspensions, and intravenously in alkaline 

• For historv of the development of this idea, see EhrKch, Ztschr. I Immuni- 

tatsforsch., etc., 191 1. vol. 3, p. 1 123. 

; I I,, London, at the international Con-res-. Tgersheimer reiterated this claim, 
and a careful Bearch of the available ophthaunological literature has failed to show 
any case of such toxic action of salvarsan on the eye. Tb.] 



538 ETIOTROPIC PHARMACOLOGICAL AGENTS 

solutions. The intravenous injection acts most quickly and intensely 
on the symptoms of the early stages, but when injected subcutaneously 
it remains for a very long time at the place of injection, and when 
injected intramuscularly is somewhat more rapidly absorbed. In both 
of these latter cases it appears to form a deposit from which it is more 
or less regularly and gradually absorbed into the body, but, owing to 
the extreme irritation caused by its long-continued contact with the 
tissues, such injections cause severe and persistent pain, with lasting 
infiltration and often extensive necrosis. Consequently, Ehrlich more 
recently recommends that it be administered in alkaline solution ex- 
clusively by the intravenous route in doses ranging up to 0.6-0.8 gm. 

It would appear that a general internal disinfection may be more 
certainly obtained by a single or several times repeated injection 
of salvarsan than is attained when it is injected subcutaneously or 
intramuscularly, in which case it forms a deposit from which it is 
very gradually absorbed. This is in accord with the experience 
obtained in animals, that the parasites which have withstood the first 
attack of the remedy acquire a relative immunity to it. 

After intravenous injection salvarsan is eliminated rather rapidly, 
but when injected subcutaneously, while the elimination starts very 
soon, it continues for about fourteen days, and after intramuscular 
injection somewhat longer (Greven). After intramuscular injection 
chickens remain immune to infection with spirillosis for 30^0 days, 
but after intravenous injection the protective effect disappears in 
3-4 days (Hat a). 

That salvarsan exerts an etiotropic action on human syphilis is 
indicated in the first place by the rapid disappearance of the spirochetes 
following its injection. In addition, this is indicated by the fact that 
the blood-serum of patients treated with salvarsan appears to contain 
specific antibodies which exert a curative effect in children with heredi- 
tary syphilis (Scholtz and others). According to Ehrlich, the forma- 
tion of these antibodies is due to the destruction of the parasites by 
this remedy, their decomposition products stimulating the organism 
to form antibodies; but, according to Friedberger, salvarsan itself 
directly and markedly stimulates the formation of antibodies. 

Salvarsan has also proven itself an efficient etiotropic remedy in 
other spirochetal diseases, particularly in relapsing fever (Iversen). 

This is not the place to enter into a discussion of the respective 
fields and limitations of salvarsan and mercury in the treatment of 
syphilis. A combined alternating treatment with these two remedies * 
would appear to be theoretically indicated by the experiences obtained 
by "combination therapy" in experimental trypanosomiasis and 
spirochetal infections (Tsuzuki). These have shown that the com- 
bination of several etiotropic substances produces a more energetic 

* [Practical experience has proven the correctness of this theory. — Tb.] 



ARSENIC AND MERCURY IN SYPHILIS 539 

effect and a more certain cure than would be expected from the arith- 
metical sum of the effect of the different substances used. Such alter- 
nating treatment with arsenical and mercurial preparations would 
appear to be indicated by the fact that the resistance acquired by cer- 
tain protozoa to one group of etiotropic remedies does not extend to 
remedies of a different nature, and consequently it is probable that 
those parasites which have become resistant to one remedy and which 
are responsible for recidivation may be destroyed by remedies of a 
different nature. 

BIBLIOGRAPHY 

Binz u. Schulz: Arch. f. exp. Path. u. Pharm., 1879, vol. 11, p. 200. 

Blumenthal: Med. Klinik, 1907, No. 12. 

Ehrlich: Verhandl. d. deut. derrnatolog. Ges., 1908. 

Ehrlich: Bericht d. deut. chem. Ges., 1909, vol. 42. 

Ehrlich: Ztschr. f. Immunitatsforschung u. exp. Ther., 1911, vol. 3, p. 1123. 

Ehrlich u. Bertheim: Ber. d. deut. chem. Ges., 1907, vol. 40, p. 32. 

Ehrlich u. Hata: Die exp. Chemotherapie d. Spirillosen, Berlin, 1910. 

Ehrlich u. Shiga: Berl. klin. Woch., 1904, No. 13. 

Friedberger: Berl. klin. Woch., 1908, No. 38. 

Friedberger: Therap. Monatsh., 1911, May. 

Greven: Munch, med. Woch., 1910, No. 40. 

Harnack: Arch. f. exp. Path. u. Pharm., 1878, vol. 9, p. 158. 

Heffter: Arch. f. exp. Path. u. Pharm., 1901, vol. 42, p. 230. 

Hepp: Arch. f. exp. Path. u. Pharm., 1887, vol. 23, p. 91. 

Husemann: Deut. med. Woch., 1892, p. 1137. 

Igersheimer: Munch, med. Woch., 1910, No. 51. 

Igersheimer: Schmiedeberg-Festschrift, Arch. f. exp. Path. u. Pharm., 1908. 

Igersheimer u. Rothmann: Ztschr. f. physiol. Chemie, 1909, vol. 59, p. 256. 

Iversen, in Ehrlich-Hata: Die exp. Therapie d. Spirillosen, Berlin, 1910. 

Koch, R.: Deut. med. Woch., 1907, No. 33. 

Laveran u. Mesnil: Annal de l'lnstitut Pasteur, 1902. 

Loew, O.: Plliiger's Arch., 1887, vol. 40, p. 437. 

Marks: Ztschr. f. Immunitatsforschung u. exp. Ther., 1909, vol. 2. 

Muto: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 494. 

Neuhaus: Arch, intern, de Pharmacodyn., 1910, vol. 20, p. 393. 

Rohl: Ztschr. f. Immunitatsforschung u. exp. Ther., 1909, vol. 1. 

Rohl: Berl. klin. Woch., 1909, No. 11. 

Scholtz: Deut. med. Woch., 1910, No. 41. 

Thomas: Brit. Medical Journal, 1905. 

Tomasczewski: Berl. klin. Woch., 1910, No. 33. 

Tsu/.uki: Ztschr. f. Hyg. u. Infektionskrankh., 1911, vol. 68, p. 364. 

Uhlenhut: Deut. med. Woch., 1907, No. 4. 

Uhlenhut: Med. Klinik, 1911, No. 5. 

Uhlenhut u. Manteufel: Ztschr. f. Immunitatsforschung, 1908, vol. 1. 

MERCURY AS A SPECIFIC FOR SYPHILIS 

Historical. — Mercury has long been considered a specific against 
the secondary symptoms of syphilis. After having been used even 
earlier in the Orient, mercurial preparations about the year 1500 
became generally recognized as efficient in syphilis when administered 
internally. At this time mercury was pushed up to the appearance 
of severe toxic symptoms, such as salivation, diarrho>a, etc, so that the 
dangers which accompanied the treatment soon led to a reaction, as a 



540 ETIOTROPIC PHARMACOLOGICAL AGENTS 

result of which physicians in the sixteenth century were divided into the 
two camps of rnercurialists and anti-mercurialists. Gradually, how- 
ever, this opposition, which persisted even into the nineteenth century, 
has disappeared as physicians have learned how to use the remedy 
rationally. 

Its Etiotropic Action. — That mercury exerts an action on the 
causative agent of syphilis is rendered probable by the fact that the 
most varied symptoms of the infection are equally influenced by it 
and that healthy children may be born of syphilitic parents who have 
been treated with mercury, while, when the parents have not been 
treated by mercury, their children are congenitally syphilitic. Thus 
far it has not been definitely proven that this action on the Spiro- 
chaeta pallida is etiotropic in the same strict sense as is the action of 
quinine on malarial plasmodia, for an indirect action on these para- 
sites by stimulating of the formation of antibodies is conceivable. 
However, it is more probable that this drug acts directly on the 
pathogenic organisms, for, in general, cures result the more certainly, 
the more completely and persistently the body of the patient is kept 
saturated with mercury to the degree of tolerance. It is a recognition 
of this fact which has led to the general adoption of the chronic 
intermittent mercury treatment, in which the infected individuals are 
kept under the influence of mercury off and on for several years. 

The excretion of mercury in the urine offers a means of estimating 
the amount of mercury circulating in the body and the duration of its 
action. While after absorption mercury circulates about in the body 
as a compound of mercury-albuminate and sodium chloride, and is 
chiefly excreted in the freces and to only a small extent in the urine, 
still that portion of the mercury which is present in the general circu- 
lation, and which passes through the renal vessels, probably maintains 
a definite ratio to the amount excreted in the urine. The more rapidly 
the mercury appears in the urine after its administration in the given 
method the more rapidly and intensely are its effects produced, and 
the more rapidly its elimination by this channel diminishes the more 
rapidly does its action in the body pass off. Always, however, it con- 
tinues to be excreted for months, and, under certain circumstances, 
after the urine has become free from mercury it may appear in it 
again, both of these facts proving that mercury is stored up in differ- 
ent organs, as a result of which poisoning must sooner or later result 
if the elimination fails to keep pace with the absorption. 

The aim of every energetic antiluetic mercurial cure must be to 
maintain for a considerable time the mercury content of the organism 
at such a height that, while not causing toxic effects, it remains not 
too far below this toxic concentration. A regular elimination of 
mercury during the period of administration and a gradual sinking 
of the curve of elimination after its cessation may serve as signs that 
one is close to the attainment of such saturation. A temporary marked 



MERCURY AS SPECIFIC FOR SYPHILIS 541 

increase in the amount eliminated, either directly after its adminis- 
tration or in the course of the cure, indicates a too rapid absorption, 
-with its accompanying danger of poisoning. 

The determination of the curve of elimination is, consequently , o'f 
importance for the determination of the value of different methods of 
administering mercury (Bilrgi). 

When mercurial inunctions are given (of mercurial ointment 33 
per cent., daily 3.0-5.0 gm. for 30-40 days), mercury may be 
recognized in the urine from the first day on, its elimination increas- 
ing gradually up to a certain point and then remaining for weeks 
very nearly constant, and, after cessation of treatment, falling again 
very gradually. The absorption of mercury from the ointment is due 
in part to the gradual change of the metal, which has been pressed 
into the openings of the ducts of the glands of the skin, into mercuric 
salts of the fatty acids, or to its gradual change into these same salts 
by the oxygen of the air acting under the influence of the secretions 
of the skin. As this chemical transformation occurs very gradually, 
local irritation does not, as a rule, occur. The mercury is also to some 
extent absorbed through the lungs as a result of respiring such of it 
as is vaporized by the body heat. 

By Inhalation. — When present on the surface of the skin, metallic mer- 
cury vaporizes in sufficient quantities to produce therapeutic effects solely as a 
result of its absorption through the lungs. On this fact is based the employment 
of mercurial amalgam, a gray powder composed of aluminum and magnesium 
amalgam, which is kept in contact with the skin in a small bag and thus pro- 
vides a mild mercurial treatment. When thus used its elimination follows essen- 
tially the same course as in a mild inunction cure. 

Oral, Administration. — When mercury is to be administered by 
mouth, the mercurous compounds are usually employed, particularly 
calomel, HgCl (0.03-0.05 gm. ter in die, at times combined with 
opium), and the yellow iodide of mercury, which is used in the same 
dosage as calomel, and which is particularly often used in children, 
in a dosage for infants of 0.01 gm. per diem. Although in vitro the 
mercurous compounds are insoluble in water, in the body they are 
absorbed, but when they are administered internally the amount of 
mercury eliminated in the urine shows very marked variations from 
day to day, due apparently to the varying conditions affecting absorp- 
tion from the intestine. The suddenly increased absorption which 
may occur when Ilg is thus administered explains the greater danger 
of causing mercurialism when mercury is administered internally, 
and when it is tlius administered stomatitis and diarrhoea are observed 
relatively often. 

For mercurial injections soluble and insoluble preparations are 
used. 

Of the soluble ones the bichloride is the one most used, in daily 
small doses of 0.03 '-'in. continued for 20—40 days. Its excretion in the 
urine starts at once, and if t he injections arc given each day the 



542 ETIOTROPIC PHARMACOLOGICAL AGENTS 

amount eliminated rises gradually and regularly just as is the case 
in inunction cures, and when its administration is stopped the amounts 
eliminated gradually decrease, its elimination curve corresponding to 
that of a gradual saturation. Unfortunately, these injections in many 
cases cause pain and induration, even when by addition of sodium 
chloride the attempt is made to prevent the precipitation of mercury 
albuminate at the point of injection. 

These local effects cannot be certainly avoided, even by the use of organic- 
compounds of mercury with formamide, glycocoll, etc., which are soluble in 
alkaline media. 

Finely divided insoluble mercurial preparations, such as calomel, 
thymol-acetate of mercury, salicylate of mercury, etc., are injected 
(suspended in liquid paraffin or olive oil) in amounts of 0.05 to 0.1 
gm., at considerable intervals, — about every six to seven days, — with 
the idea of forming a deposit of mercury from which absorption will 
take place gradually. As a matter of fact, however, the elimination 
curve after injection of the widely used salicylate of mercury does not 
indicate a gradual regular saturation of the organism with mercury, 
but, on the contrary, the maximal elimination occurs on the day of 
injection and sinks immediately, rising with each new injection. 
This curve of elimination is in accordance with the clinical experience 
that, although these injections are very efficient, they are at times dan- 
gerous, for a serious poisoning may result from the unexpected sudden 
absorption of large amounts of mercury from the reactively inflamed 
tissues around the mercurial deposits. 

After intravenous injection of the bichloride, the curve of elimination 
rises abruptly and falls again very quickly. When thus administered more than 
50 per cent, is rapidly eliminated from the body, and for a time so much mercury 
is present in the circulation that the danger of causing toxic symptoms is neces- 
sarily great, not to speak of the danger of the formation of thrombi. 

From the above it is apparent that inunction cures best meet the 
demand for a gradual and even mercurialization. [The translator is 
among those who are convinced that hypodermic injections of soluble 
mercurial preparations have been proven to be the most rapid and 
certain means of curing syphilis by mercury. The observations on the 
disappearance of the Wassermann under various methods of treat- 
ment, as well as the observations on its reappearance or failure to 
reappear, both appear to indicate that this conclusion, which has 
been based on clinical experience, is well founded. — Tr.] However, 
even when mercury is thus administered, it is not always possible to 
avoid the symptoms of poisoning. These start with a metallic taste 
in the mouth, stomatitis, and salivation (see p. 513). Albumi- 
nuria and nephritis * may also develop during mercurial cures, and 
in severe poisoning diarrhoea occurs. In fatal cases cardiac depres- 
sion, sinking of the blood-pressure, and collapse may result. 

* [Albuminuria and nephritis are not infrequently manifestations of syphilis, 
the occurrence of which during the mercurial cure is, the translator believes, 
quite as often, or more often, due to the disease than it is to the remedy. — Tb.] 



ANTITOXINS 543 

BIBLIOGRAPHY 
Biirgi: Arch. f. Dermat. u. Syphilis, 1906, vol. 79. 

ANTITOXINS 

Historical. — The experimental therapy of infectious diseases had its 
origin in the study of the problems of immunity.* In his studies of 
acquired immunity Pasteur, having observed that many infectious 
diseases attack the same individual but once and that in such cases 
a very light attack appears to give the same protection as a severe 
one, started a series of logically planned laboratory experiments in the 
hope of finding methods of treatment which, like light attacks of ill- 
ness, would give the same immunity without injuring the animals ex- 
perimented on. He strove to reach the same goal as had been attained 
empirically by Jenner when he utilized the chance observation that the 
harmless cowpox protected against the dangerous human smallpox. 

In 1880 Pasteur succeeded in immunizing animals against the viru- 
lent pathological organisms of chicken-cholera, and soon afterwards of 
anthrax, by inoculating them with artificially attenuated bacteria. 
The discovery that the virulence of microbes may be increased or 
diminished by their passage through animals was of great importance 
in Pasteur's later success in discovering his method of inoculation 
against rabies. The Americans, Salmon and Smith, while investigat- 
ing hog-cholera, 1885-86, were the first to learn that immunization 
could be produced by injecting not only attenuated bacteria, but also 
their soluble metabolic products, known to-day as toxins. Later on, 
immunization against the bacilli of tetanus and diphtheria was accom- 
plished by Roux and by Brieger and Kitasato, who injected filtrates 
from bacterial cultures for this purpose. While in other cases it was 
mt possible to produce immunity by use of the metabolic products of 
living bacteria, if the bacteria first be killed, it is possible to produce 
immunity by injecting the substance contained in the dead bodies, the 
endotoxins. This was first done by Pfeiffer using cholera vibriones. 

Further progress in the study of the problems of immunity was 
rendered possible by the discovery that the inoculation of animals 
with gradually increasing amounts of bacterial substances produces 
an immunization not only against the living pathological organisms, 
but also against the injection of large quantities of the same extremely 
toxic substances with which they are inoculated. As a result of the 
recognition of this fact, it became possible to investigate these problems 
by quantitative methods. 

* In this con no o.t ion tlio authors will confine themselves to a discussion 
of those points bearing on immunization which are essential for the understanding 
of the nuw generally adopted method of treatment. More complete discussions 
may he found nol only in various monographs and larger works, but in the 
following works: Krehl u. Levy, Sap. [nfektion und [mmunit&l in Erehl's Pathol. 
Physiologic, 5. Aull., Leipzig, 1907; .1/. Jakobjf, Immunitiit und Disposition, 
Wiesbaden, 1900; <)]>])( nhiimir, Toxiue und Ant itoxine, Jena, 1904; Th. Wilier, 
Infcktion und I mmunitai . Jena, 1904; DieudonnS, [mmunitat, Schutzimpfung 
und Serumtherapie, 6. Aufl., Leipzig., 1909. 



544 ETIOTROPIC PHARMACOLOGICAL AGENTS 

Active and Passive Immunity. — Soon after Pasteur, Cliauveau, in 
1881, showed that it was possible to produce immunity by the injec- 
tion of living pathogenic organisms of full virulence, for the natural 
protective powers of the organism are able to maintain the upper hand 
in the strife against bacteria, providing the number of these be small 
or if the conditions for their multiplication be unfavorable. If the 
organism overcomes the infection or the poisoning by toxins, it be- 
comes immune as a result of the activity of its own protective mechan- 
isms, which form antitoxin and other protective substances. This type 
of immunity, resulting from the activity of the organism itself, is 
known as active immunity, the specific immune bodies thus formed 
circulating about in the blood, as has been known ever since Behring's 
discovery of the antitoxins. Passive immunity, which results from the 
introduction into an animal of such already formed immune sub- 
stances, is thus named because it is produced without any aid from the 
individuals rendered immune. 

"While in active immunity a certain period, usually from five to 
ten days (v. Dungcrn), must elapse before the development of im- 
munity, passive immunity is conferred immediately by the adminis- 
tration of the protective serum. Active immunity persists for a very 
long time, as those reactions of the cells which result in the formation 
of the immune bodies persist for a long time and endow the organism 
with the power of making good the loss of its protective substances. 
Passive immunity, on the contrary, persists for a much shorter time, 
for the substances which have been derived from actively immunized 
individuals are foreign substances for the passively immunized organ- 
ism, and are therefore eliminated or combusted and are not replaced 
by the organism. 

In human medicine, except for vaccination against variola and 
more recently against typhoid, active immunization is employed only 
for the treatment of rabies. 

BIBLIOGRAPHY 
v. Dungern: "Die Antikorper," Jena, 1903. 

VACCINATION AGAINST RABIES 
This disease, the pathogenic organism of which is not yet known, 
is remarkable for its long period of incubation; but Pasteur discov- 
ered that the period of incubation may be very strikingly shortened 
by injecting the virulent substances, obtained from the central 
nervous system of rabid animals, directly into the central nervous 
system instead of into other parts of the body. This shortening of 
the incubation depends, as we know to-day, on the fashion in which 
the toxic substances are distributed throughout the body, for these 
reach the point at which they act, the central nervous system, through 
the peripheral nerves, the disease developing only when the poisonous 
substances have reached these centres. 



VACCINATION AGAINST RABIES 545 

These findings of Bales and of de Yestea and Zagari, however, left it unset- 
tled whether it was the pathogenic organisms themselves or the poisons produced 
by them which thus travelled along the nerves. Since, however, Hans Meyer and 
Ransom have shown that tetanus and diphtheria toxins are carried to the central 
nervous system by the nerves, it may be assumed that direct inoculation of the 
rabies virus into the central nervous system shortens the period of incubation, 
because in this case the poison itself does not have to pass along these paths. 
The more virulent the virus the more rapidly is the toxin manufactured, and 
consequently the shorter is the period of incubation, but even with the most 
virulent virus a certain length of time is needed for the journey to the central 
nervous system, varying with the length of the nerve path and amounting in the 
rabbit to 7-8 days and in the guinea-pig to 5-6 days. 

By appropriate passage of the virus through a series of animals 
or by heating it in the absence of moisture for varying periods, 
Pasteur obtained viruses of varying virulence and incubation period, 
and, by inoculating animals first with the weak viruses, he was finally 
able to render them actively immune against the most virulent viruses. 
In animals thus actively immunized the blood contains protective 
substances, for when such serum is inoculated into other animals it 
protects them also (Babes et Lepp). Owing to the fact that the 
rabies organism is unknown,* it cannot to-day be stated whether these 
protective substances protect against the toxins produced by this 
organism or against the organism itself (Marx). 

In any case the efficiency of the Pasteur prophylactic treatment of 
rabies is to-day established beyond question. As the treatment is 
necessarily always inaugurated only after infection has occurred, it is 
evident that the protective substances which are produced during 
immunization must reach the toxins manufactured at the point of in- 
fection before they are carried to and become combined with the 
nervous centres. When the treatment is instituted promptly this is 
possible, probably because the multiplication of the pathological organ- 
isms and the manufacture of the toxins at the infected point go on 
very slowly. 

BIBLIOGRAPHY 

Babes u. Lepp: Ann. de l'Inst. Pasteur, 1889, vol. 3. 

de Vestea u. Zagari : Ann. de l'Inst. Pasteur, 18S9, vol. 3. 

Harris: Journ. of A. M. A., 1913, vol. 01, p. 1511. 

Marx: in Kolb-Wassermann's Hdb. d. Infektionskrankheiten, vol. 4, p. 12G4. 

Moon: Journ. of Inf. Dis., 1913, vol. 13, p. 232. 

NToguchi: Journ. Exp. Med., 1913, vol. 17, p. 29. 

Poor and Bteinhardt: Journ. Inf. Dis., vol. 12, p. 202; vol. 13, p. 203. 

Williams: Journ. of A. M. A. 1913, vol. 61, p. 1509. 

Williams: Journ. of Inf. Dis., 1913, vol. 13, p. 165. 

TUBERCULIN 
Tuberculin treatment is also based upon active immunization 
(Sahli). The various tuberculins are endotoxins which may be ex- 

* [Recent investigations by Moon, Noguohi, Poor and Btevtlhord and Williams 
make it probable thai this organism is no longer to be numbered among the 
unknown pathological agents. Moon and Harris both report curative efTects 
from quinine in this disease. — Tb.] 
35 



546 ETIOTROPIC PHARMACOLOGICAL AGENTS 

tracted from the bodies of the bacteria only after their death. The 
various preparations used in practice either, like old tuberculin, con- 
tain those constituents of the dead bacteria which are soluble in 
glycerin and water, or, like new tuberculin, they consist of a suspension 
of very finely pulverized dead bacterial bodies. With new tuberculin 
Koch has been able to immunize animals against ordinarily lethal 
infection with tubercle bacilli. 

When introduced into the body tuberculin causes both a systemic 
reaction and one localized in tubercular tissues. It is the different 
intensity of the reaction produced by tuberculin in normal and in 
tubercular animals and human beings which is responsible for the 
clinical significance of the various diagnostic tests (Koch). While 
tubercular tissues exhibit a similar hypersusceptibility to certain other 
substances, such as cantharidin and the albumoses, still there are quan- 
titative differences which make it apparent that the reaction of tuber- 
culin is a specific one (see p. 490). Tins specifically altered suscep- 
tibility is known as allergy, and in the case of tubercular tissues is 
attributed by v. Pirquct and Schick to the presence of a specific anti- 
body for tuberculin (Moro) . According to Wolff-Eisner, this anti- 
body sets free from the tuberculin certain substances which produce 
an augmented endotoxin action. 

BIBLIOGRAPHY 

Koch, R.: Deut. med. Woch., 1800 and 1897: 1801, No. 3. 

Moro: Exp. u. klin. Ueberempfindlichkeit, Wiesbaden, 1910. 

v. Pirquet u. Schick: Wien. klin. Woch., 1903, No. 45. 

Sahli: Die Tuberkulinbehdlg. n. Tuberknloseimmunitat, Basel, 1910. 

Wolff-Eisner: Berl. klin. Woch., 1904, No. 42. 

SERUM THERAPY 

Serum therapy depends upon the fact that protective substances, 
which have been formed during active immunization in one animal, 
may be injected into a second one (a human being) . Before discussing 
the principles of serum therapy and the limits of its efficiency, it will 
be necessary to describe our present conceptions of the nature of toxins 
and antitoxins and of their reciprocal relationships. 

Toxins. — The conception of toxins arose when powerful toxic sub- 
stances were found in the pathogenic micro-organisms and their toxico- 
logical significance was recognized. At the start there were found in 
the filtrates from bacterial cultures soluble poisons, which produced 
the same symptoms as the pathogenic organisms themselves (Roux et 
Yersin, Briegcr u. Frdnkel). Later substances with similar toxic 
properties were found in the bodies of the bacteria and also in certain 
poisons of animal origin and in certain vegetable seeds. These were 
at first thought to be true proteids, because they could be precipitated 
from their solutions along with the proteids also present therein. 
However, we actually know nothing of their true chemical nature, as 



SERUM THERAPY 547 

no one has thus far succeeded in preparing toxins in pure form and 
consequently our conception of the toxins is only a biological one. 

These toxins are poisonous substances possessing the power of 
stimulating the organism to form specific antidotal poisons or anti- 
toxins. TYe know of them that they diffuse with difficulty or not at all, 
and that consequently they are either themselves colloidal substances 
or, as a result of combination with proteid substances, have acquired 
colloidal properties. Most of them are very susceptible to heat and 
light and to exposure to air and are chemically very labile. It is very 
possible that they actually are proteids, for their most characteristic 
property, that of stimulating the organism to form specific substances 
which react with them, is also a property of non-toxic proteids in so far 
as these reach the blood without being denatured. Moreover, like the 
proteids, the toxins are acted on by enzymes or ferments, a fact which, 
taken with the slight absorption of some of them, explains their rela- 
tive harmlessness when swallowed. 

Toxins also show very close analogies with the ferments, of whose 
chemical nature we know quite as little. These, too, excite the produc- 
tion of specific antiferments in the organism, and are characterized, 
like the toxins, by the property of exerting their actions only on cer- 
tain specifically susceptible substances. Like the ferments, the toxins 
also are perhaps protoplasmoid, — that is, they too may possess certain 
properties of living proteid. 

From the above it may be seen that our knowledge of toxins is 
limited to a knowledge of their toxic actions and of their power of 
stimulating the body to form specific antitoxins. As already men- 
tioned, poisons of this type are formed not only by bacteria, for certain 
poisons of animal origin behave in an entirely similar fashion, — for 
example, the venom of certain toads, spiders, snakes, scorpions, and 
bees, and many toxins derived from fishes. In addition, similar sub- 
stances, known as phytotoxins, occur in plants, — for example, ricin 
in ricinus beans, crotin in croton seeds, and abrin in jequirity beans. 

Antitoxins. — The antitoxins were discovered in 1890 by Bchring 
and Kitasato, who showed that animals could be immunized by the 
injection of the blood-serum of other animals which had been actively 
immunized against tetanus and diphtheria. Soon after, in 1891, 
Ehrlich showed the same for ricin poisoning. As the serum of the 
actively immunized animal does not contain even traces of toxin which 
could produce active immunity in the second animal, it was evident 
that during active immunization a new substance must have been 
formed either out of the original toxin or from the body cells or 
from both together. This new substance acts specifically with the toxin 
which has been used to produce active immunization, and with no 
other. 

Nothing is known of the chemical nature of these antitoxins, but 
it is practically certain thai liny are colloids "I" distinctly greater 



548 ETIOTROPIC PHARMACOLOGICAL AGENTS 

molecular weight than the toxins, for they diffuse much more slowly 
than do these (Arrhenius Madsen), Antitoxins, too, are chemically 
labile, although in general more stabile than the toxins, and many of 
them are not destroyed by heating up to 60° C, and even, depending 
upon the amount of salt present in their solutions, up to nearly 80° C. 
They are also more resistant than the toxins to the action of acids 
and alkalies, and are not so readily decomposed by exposure to light 
and air. 

From the above it is clear that the antitoxins also can be character- 
ized only biologically. They are reaction products of the organism 
which are produced under the influence of toxins, and which act 
specifically with and render harmless only the toxin which has stimu- 
lated their formation. We know nothing of their other actions in the 
body. 

The Specificity of the Reaction between Toxins and Anti- 
toxins. — In vitro the blood-serum of an animal immunized against 
diphtheria can render harmless only diphtheria toxin, but not tetanus 
or other toxins, and can protect other animals only against lethal doses 
of diphtheria toxin but not against those of other toxins. To explain 
this it might be assumed, with Buchner, that both antitoxins and toxins 
react with those body cells which are susceptible to the toxins, and that 
the antitoxins when injected previously to or simultaneously with the 
toxins are able to interfere with the action of the latter by a physio- 
logical antagonism. To-day, however, we know that Ehrlich's and 
Behring's view is the correct one, and that the antitoxin exerts no 
direct action on the body cells but reacts only with the toxin. In this 
reaction the toxin is not destroyed by the antitoxin, as was at first 
believed ; but the reaction between the two substances consists rather 
in a reciprocal fixation or combination which takes place in accord- 
ance with fixed quantitative conditions, as has been shown by Ehrlich 
for ricin and diphtheria toxins and their antitoxins. This reaction 
needs a certain time for its completion and proceeds more rapidly at 
high temperatures than at low. Whether the combination between 
toxins and antitoxins is to be conceived of as analogous to the combina- 
tion between weak bases and weak acids, or whether the toxin-antitoxin 
reaction is reversible only with difficulty or not at all, is still the sub- 
ject of active discussion (see Arrhenius). 

That the detoxication of toxins by antitoxins is actually due to the 
formation of a non-toxic compound is proven by the fact that in cer- 
tain cases it is possible to separate the toxin and the antitoxin from 
the compound which has been formed. Thus, Roux and Calmette were 
able, by boiling a non-toxic mixture of snake venom and antitoxin, to 
render it poisonous again, for this antitoxin is readily destroyed by 
boiling while the venom supports high temperatures much better. 
Further, Morgenroth has recently succeeded in separating diphtheria 
toxin from its combination with the antitoxin by allowing acids to 



SERUM THERAPY 549 

act upon the compound. Finally, in certain cases either the free toxin 
or free antitoxin diffuses through certain membranes, although the 
mixture of the two is unable to do so (Martin and Cherry) . 

Formation of Antitoxins. — The manner in which antitoxins are 
produced is entirely unknown. Their specificity suggested that they 
were formed from the toxins (Buchner), — that is, that the organism 
had the power of changing the toxins into antitoxins, which could 
render harmless toxins subsequently administered. If this were so, 
however, one would expect that there would be some quantitative re- 
lationship between the amount of toxin administered and of the anti- 
bodies formed. Knorr, however, has shown that, after the injection of 
a certain amount of tetanus antitoxin, the body produced enough 
antitoxin to neutralize 100,000 times as much toxin as had been 
administered. Further, Roux and Vaillard, by repeatedly bleeding 
horses immunized against tetanus, have been able to remove from 
them amounts of blood equal to the total original blood content of the 
animals, without materially lessening the antitoxic power of the 
blood-serum. It is also known that other antibodies related to the 
antitoxins, such as the agglutinins present in the blood-serum of men 
who have recovered from typhoid, may be demonstrated in these 
individuals for months and years, although the fate of the already 
formed antibodies introduced from without shows that they are grad- 
ually destroyed or eliminated and disappear entirely. It is, therefore, 
clear that in actively immunized animals the antitoxins must continue 
to be manufactured for a very long time. Thus, the quantitative 
disproportion between the toxin administered and the antitoxin pro- 
duced and the continuation of the formation of antitoxin without 
further administration of toxin both render it highly probable that 
the antitoxins are products of the metabolic activity of the cells. 

Antitoxins are, therefore, to be looked upon as produced by specific 
but still completely unexplained active processes in the body cells, 
which are excited by the toxins. Once these reactions have been 
inaugurated, they may persist much longer than their inaugurating 
stimulus, and, as is the case with other effects of stimuli, there is not 
necessarily any fixed proportion between the amount of toxin adminis- 
tered and the products of the reaction thus excited. 

Practically nothing is known as to the place where antitoxins are formed. 
The blood ia looked upon simply as the place where they accumulate, but not 
as the place where they are formed. Of the various organs it has been possible 
only to show that the lymphoid tissues contain protective substances at the com- 
mencement of active immunization before these may be detected in the serum 
. r ". Marco, Waaaermann, Ronn r | . 

ANTIGENS AND Axtibodies. — The formation of antitoxin is only a 
special inst;in<-«- of ;i general reaction which follows the entrance into 
the blood of proteid substances which h;ive not been denatured, for it 
is a general rule that, when such substances penetrate into the blood, 



550 ETIOTROPIC PHARMACOLOGICAL AGENTS 

the organism forms reaction products which react specifically with 
them. Thus, after the parenteral introduction of heterologous proteids, 
— whether these, like the proteids of bacteria, are toxic, or whether, 
like heterologous serum, albumen, lacto-albumen, etc., they are rela- 
tively non-toxic, — precipitins appear in the bloocl-serum, which react 
specifically with the proteids in question and form insoluble products 
with them. When bacteria are injected, bacteriolysins are formed, 
and, when normal cells are injected, specific cytolysins or agglutinins. 
In these instances the reaction between the antibodies formed in the 
blood and the antigens — that is, the foreign substances which excited 
the reaction — are directly visible. The presence of other antibodies, 
as these specific reaction products are generally named, — for example, 
that of the antiferments, — may be recognized in the serum only by the 
fact that they inhibit the activity of the antigens, — i.e., in the case 
of the ferments they inhibit their ferment action. In the same way 
the presence of antitoxins is recognizable only from the fact that the 
serum prevents the toxic action of the toxins. 

EHRLICH'S SIDE-CHAIN THEORY 
While we actually know nothing of the manner in which antibodies 
are produced, according to the views advanced by Ehrlich and now 
accepted by most investigators, the antibodies normally exist as ' ' side- 
chains" in the cells which produce them. According to the hypoth- 
esis, certain atom groups of the protoplasm react with the antigen 
introduced, and these same atom groups under the influence of the 
reaction are manufactured anew in increased amounts and pass into 
the blood as soluble reaction products which act as antibodies. So 
long as these reacting protoplasmic groups remain combined with the 
cells, they attract the antigens to the cells, — i.e., they attract the 
toxins to the point at which they exert their toxic action. When, how- 
ever, they are present in the blood as antitoxins, by their affinity to 
the toxins they divert them from their point of reaction, the specifically 
susceptible elements in the cells. 

Toxoids. — A matter of great importance in the further development of the 
theories of immunity was the behavior of certain substances which are readily 
formed from the toxins, and which, while relatively non-toxic, are still able to 
combine with antitoxin. 

Ehrlich, during his investigations of diphtheria toxins, was the first to find 
such substances, named by him toxoids. This author found that there was a 
parallelism between the toxic action and the power of combination with antitoxin 
only in freshly prepared solutions of diphtheria toxins, and that, when the solu- 
tions were allowed to stand for a time, their toxicity decreased, but their power 
to neutralize antitoxin persisted, as did that of stimulating the formation of 
antitoxin. To explain these facts Ehrlich assumes two types of atom groups in 
the toxin molecule, — a combining or haptophoric group, by which the toxin is 
anchored to the cell protoplasm and by means of which it combines with antitoxin, 
and a toxophoric group, the loss of which robs the toxin molecule of its typical 
toxic actions. These toxophoric groups are lacking in the toxoids, which, how- 
ever, through their haptophoric groups are still able to attach themselves to the 



EHRLICH'S SIDE-CHAIN THEORY 551 

protoplasm of the cells, thus stimulating the production of antibodies, and to 
react with the antitoxin in the same way as the entire original toxic toxin 
molecule. 

This parallelism, between the capacity of combining with antitoxin in vitro 
and that of exciting the formation of antitoxin, led Ehrlich to assume that the 
same atom groups are responsible for the combination of antigen with antitoxin 
and for its reaction with the cells of the organism, and, according to his theory, 
this stabile combination between toxin and cell protoplasm is the cause of the 
production of antibodies, while the typical toxic action of toxin has nothing 
to do with it. The fact that the production of antibodies may be excited by 
toxoids as well as by toxins is thus explained, as is also the fact that the 
toxins excite their production only in case the cells are not too severely damaged 
by their toxic action. In accordance with this assumption, those cells which 
have not been at all damaged by the specific toxic action of the toxin can also 
take part in the production of antitoxin, if the toxin simply combines with their 
protoplasm. 

It is thus apparent that, according- to Ehrlich' s side-chain theory, 
the antibodies are those atom groups of the protoplasm which react 
in the cells with the antigens and are then formed in excessive amounts 
and cast off into the blood. This theory, however, does not tell us why 
the superfluous new formation and casting off of side chains occurs 
during the manufacture of antibodies. Ehrlich himself draws an 
analogy between the phenomena resulting from damage to the proto- 
plasm by foreign substances and the morphological phenomena 
observed following trauma of the tissues, in which not only the cells 
which have perished are replaced but in which there always occurs 
a distinct over-production. 

BIBLIOGRAPHY 
Arrhenius: Immunochemie in Ergebn. d. Pbysiologie, 1908, vol. 7, p. 480. 
Aschoff: Die Reitenkettentheorie, Jena, 1902. 
Behringu. Kitasatu: Deut. med. Woch., 1890. 
Behring u. Kitasato: Ztschr. f. Hyg., 1890. 
Brieger u. Friinkel: Berl. klin. Woch., 1890. 
Bucbner: Munch, med. Woch., 1893, p. 449. 
Ehrlich: Deut. med. Woch., 1891. 
Ehrlich: Klin. Jahrbuch, 1897, vol. 6, p. 299. 
Ehrlich: Deut. med. Woch., 1898, vol. 24. p. 38. 
Knorr: Fortschr. der Medizin, 1897, vol. 15. 
Knorr: Habilitationssclirift, Marburg, 1895. 
Martin and Cherry: Proc. Roy. Soc, 1898. 
Martin and Cherry: Brit. Med. Journal, 1898. 
Morgenroth: Virchow's Arch., 1907, vol. 190. 
Pfeiffer u. .Marx: Ztschr. f. Hyg., 1898, vol. 27, p. 272. 
IJ.mi.-r: \rch. f. Ophthal., 1901, vol. 52, p. 72. 
Rous et Calmette: Ann. de I'Inst. Pasteur, 1895, p. 225. 
Roux et Vaillard: Ann. de I'Inst. Pasteur, 1893. 
ROUS et Yersin: Ann. de I'Inst, Pasteur, 1888, vol. 2; 1889, vol. 3. 
Wassermann: Berl. klin. Woch., 1898, p. 209. 

ANTITOXIC SERA 
Antitoxic sera arc employed in the treatment of diphtheria, 
tetanus, dysentery, and snake bites. Practically the most important 
point in connection with their preparation is the securing of the high- 
est possible percentage of antitoxin in the serum of the immunized 
;iniin;ils. "By quantitative experiments, Ehrlich has been able to 
show that the higher an animal is immunized the larger the amount 



552 ETIOTROPIC PHARMACOLOGICAL AGENTS 

of antitoxin accumulated in its blood. After a latent stage of about 
5 days the antitoxin content of the serum progressively increases until 
the maximum is reached, with diphtheria at the end of 10 days and 
with tetanus at the end of 17 days, after which the antitoxin content 
sinks, to rise again after some weeks and then to remain constant for 
a long time. 

"When the immune serum is injected subcutaneously into a second 
organism, the antitoxin is slowly absorbed and remains in the blood 
for a considerable period. Thus, Knorr found that tetanus antitoxin 
attained its highest concentration in the blood only at the end of 
24-48 hours after the injection, and that the concentration then sank 
gradually so that it disappeared from the blood at the end of three 
weeks. 

It is thus seen that, while passive immunity never lasts so long as 
active immunity, a single injection of diphtheria or tetanus serum still 
confers a protection lasting for several weeks. This relatively long 
stay of the antitoxins in the blood renders it probable either that they 
are chemically closely related to the normal blood proteids or that they 
circulate about in the blood in combination with proteids (Bomer). 
Ehrlich has shown that milk contains antitoxin, and that consequently 
protective substances may be transferred from the nursing mother 
to the infant. 

Limits of Their Curative Powers. — While the antitoxins are pres- 
ent in all the body tissues, although in slighter quantities than in the 
serum, they probably do not penetrate into the interior of the cells. 
This is the case, at least, with a number of the most thoroughly studied 
antitoxins, — for example, the tetanus antitoxin and probably also the 
diphtheria antitoxin. This inability of the toxins to follow the anti- 
toxins into the cells determines the limit of the curative action of 
a serum when once the illness has developed. Probably the antitoxins 
are not able to exert any curative effects on damage which has already 
been suffered by the cells which are susceptible to the toxins, but are 
able only to prevent their further permeation with toxins and thus to 
prevent any further damage to the tissues. In the sections on the 
serum treatment of tetanus and diphtheria, the effects of the serum 
treatment of such conditions will be further discussed. 

BIBLIOGRAPHY 

Ehrlich: Deut. med. Woch., 1891, No. 32. 
Ehrlich: Ztschr. f. Hyg., 1892. vol. 12, 183. 
Knorr: Habilitationsschrift, Marburg, 1895. 
Romer: Beitr. z. exp. Therapie, 1905, No. 9. 

TETANUS 
In this disease the characteristic symptoms are not caused by a 
general invasion by the pathogenic agents, but result from the absorp- 
tion and distribution of the soluble toxins which are formed at the site 



TETANUS 553 

of the infection. Consequently, in animal experiments the symptoms 
which follow the administration of tetanus toxin are entirely similar 
to those resulting from infection with the tetanus bacilli. In man, as 
certain muscle groups are predilectively affected, the order in which 
the symptoms develop is not so regular as in animal experiments, in 
which three stages may be differentiated: 

1. Localized tetanus, a tonic stiffness of the muscles, which in most 
species of animals commences in the muscles in the neighborhood of 
the point of infection or injection. 

2. A stage in which the muscles in the neighborhood of those first 
affected are successively involved. 

3. A stage with general reflexly excitable convulsions, essentially 
resembling the convulsions caused by strychnine. 

In animals the first symptoms occur after an incubation period 
ranging from 8 hours up to a number of days. 

The effects of tetanus toxin differ from those of strychnine chiefly 
in the long period of incubation and in the occurrence of tonic muscu- 
lar rigidity, and particularly in the occurrence of a localized tetanus. 

The manner in which tetanus develops at first suggested that it 
was due to a pathologically augmented excitability of some elements in 
the periphery, but the incorrectness of this view is shown by the fact 
that curarization or section of the nerves for a time absolutely prevents 
the local contractures. These have been explained by the peculiar 
fashion in which this toxin is distributed throughout the body, H. 
Meyer and Ransom having shown that this toxin possesses a peculiar 
affinity for nervous substances, and is transported to the central 
nervous system exclusively through the peripheral nerve-endings and 
not at all through the blood. This transportation via the nerves ex- 
plains the fact that in animals the localized tetanus spreads from the 
muscles innervated by one spinal segment to those innervated by the 
neighboring segments. 

When introduced into the stomach, tetanus toxin produces no poisonous 
effects, partly because it is absorbed with difficulty but chiefly because it is 
rapidly rendered innocuous by the digestive juices, especially by the combined 
action of bile and pancreatic juice (Ransom, Carriere, Nencki). After intra- 
venous injection if disappears from Hie blood in a few minutes (Decroly), and 
after subcutaneous injection it is so quickly absorbed that rats in which it has 
been injected into the tail can no longer be saved by amputating the tail at the 
end of two or three hours, showing that the toxin must therefore be rapidly 
removed from the point of infection although the symptoms do not appear for a 
long time. By biological methods, toxin may be demonstrated in the peripheral 
nerves at the point of injection, it being present in considerable amounts in the 
Bciatic nerve l 1 - hours after injection into the leg, although at this time none 
can be demonstrated in the blood, muscles, or fat (//. Meyer u. Ransom, tforit ). 
Ah tliis elective absorption by the nerve-trunks occurs only when the axis-cylinder 

is intact,, being greatly delayed by section and entirely prevented by degeneration, 

it. is probable thai the nerve-fibrils themselves and nut the lymphatics of the 

nerves arc the path by which the toxin reaches the central nervous -\stem. 

From the above it appears that, as a result of its great affinity for 
nervous tissues, tetanus toxin is first absorbed by the intramuscular 



554 ETIOTROPIC PHARMACOLOGICAL AGENTS 

nerve-endings at the point of injection or at the point where it is 
manufactured. It is then transported by these peripheral nerves to 
the corresponding segment of the cord, from which it then spreads to 
the neighboring segments, at first to those on the injected side. 
Progressively other portions of the spinal cord become affected until, 
in the final stage, general muscular rigidity and increased reflex 
excitability develop. 

Although a portion of the tetanus toxin always passes into the 
lymph and the blood, it cannot pass from these fluids directly into the 
spinal cord, but must be absorbed by the terminal organs of other 
motor nerves, through which it then may travel to the nervous centres. 

Under experimental conditions, and also often under clinical 
conditions, the absorption in the peripheral nerves in the region of the 
injection or production of the toxin preponderates, and consequently 
cutting the nerve — for example, when the toxin is injected into 
a leg section of the sciatic — will protect the animal from ordinarily 
lethal doses. Hans Meyer was able definitely to prove that this 
toxin travelled to the centres in the nerves, by experiments in 
which he was able to block the path for the absorption of the toxin 
by previously injecting antitoxin into the nerves. Under these con- 
ditions it is detoxicated by the antitoxin as it travels along the nerves, 
so that ordinarily lethal doses produce no effects. 

It is this absorption of the tetanus toxin by the nervous tissues 
which determines the limits of the curative powers of the antitoxin. 
As the central nervous system and the peripheral nerves do not absorb 
the antitoxin from the blood, even a very large amount of antitoxin in 
the blood will not prevent animals from fatal poisoning, if the toxin 
be injected directly into a nerve-trunk, for the antitoxin can reach 
and detoxicate only that portion of the tetanus which has not yet been 
absorbed at the point of injection or production and such of it which 
although absorbed into the blood has not yet been absorbed by the 
nerve-endings. This is the reason why, although the prophylactic 
effect of subcutaneously or intravenously injected antitoxin is certain, 
its curative effect is very slight. It can cure only in case a lethal dose 
has not already been absorbed by the nerves before the antitoxin is 
injected, and consequently its effects are determined by the period 
which has elapsed between the administration of the toxin and that of 
the antitoxin. The same amount of antitoxin which, when injected 
with a many times lethal dose of toxin, certainly protects the experi- 
mental animals, fails to do this if it be administered a few moments 
later than the toxin, 40 times the amount of antitoxin being necessary 
at the end of one hour, while after the lapse of 5 hours a dose 6.00 times 
as large is ineffectual (Donitz). If a dangerously large amount of 
toxin has already been absorbed into the peripheral nerves, the pre- 
vention of the invasion of the centres by the toxin may be hoped for 
only if the antitoxin be directly injected into the nerves in the neigh- 



TETANUS 555 

borhood of the injection or site of infection. While cures have been 
obtained in a number of desperate cases by using the antitoxin in this 
f asbion, once the centres bave been attacked by the toxin, subcutaneous 
or intravenous injection of even very large amounts of antitoxin is 
almost invariably ineffectual. 

In accordance with these experimental results, clinical experience 
has also shown that, when once the symptoms of tetanus bave appeared, 
it is no longer possible to secure a cure even by enormous doses of anti- 
toxin. On the other band, tbe certain prophylactic effect of tetanus 
serum is explained by the mass action of the antitoxin in the blood 
and fluids of the body, as a result of which the toxin is kept from com- 
bining with the nervous tissues. 

The long period of incubation for tetanus has been explained by the recog- 
nition of the manner in which the toxin reaches the central nervous system 
through the peripheral nerve, and its length has been shown to depend almost 
entirely on the length of the nerve path which must be traversed before reaching 
the centres. Consequently, in larger animals the incubation period is much longer 
than in smaller ones. However, even when the toxin is introduced directly into 
the spinal cord, some time must elapse before symptoms appear. This time is 
evidently necessary for the completion of the reaction between the poison and 
the susceptible elements of the cord, for, like other ferment reactions, many toxic 
reactions also proceed but slowly. A certain temperature has also been shown 
to be necessary for this reaction. Thus, bats when kept sleeping at low tempera- 
tures manifest a very high resistance to tetanus toxin (Meyer u. Halsey), and in 
coid-blooded animals tetanus toxin under ordinary conditions remains ineffective. 
However, as shown by Courmont and Doyon, tetanus develops even in frogs after 
a certain latent period if they be kept in water at a temperature of 32° C. 
Morgenroth's experiments, in which frogs did not develop tetanus when kept 
at low temperatures but quickly did so after they had been brought into warmer 
water even a long time after the toxin had been injected, show that the toxin 
reaches tbe central nervous system at ordinary temperatures and that the high 
temperature is necessary only that the toxin may become active in the centres. 

BIBLIOGRAPHY 

Carriere: Ann. de l'lnst. Pasteur, 1899, vol. 13, p. 435. 

Courmont et Doyon: Le Tetanus, Paris, 1895. 

Decroly et Ronsse: Arch, de Pharmacodyn., 1899, vol. 0, p. 211. 

Donitz: Deut. med. Woch., 1897, p. 428. 

Marie et Morax: Annales de l'Institut Pasteur, 1902, vol. 16, p. 91S; 1903, vol. 

17, p. 335. 
.Meyer u. Iliilscy: .(alb's Festschrift, Brunswick, 1901. 
Meyer, II., u. Ranson: Arch. f. exp. Path. u. Pharm., 1903, vol. 41). 
Morgenroth: Arch, intern, de Pharmacodyn., 1900, vol. 7. 
Xeiieki, Siel.er u. Scumow-Simanowski : Zbl. f. Bakt., 1898, vol. 23, p. 480. 
Ransom: Deut. med. Woch., 1898, p. 117. 

DIPHTHERIA 

In general similar conditions influence the actions of the antitoxin 
in this disease, l>ut ihe manifold actions of the diphtheria toxin furnish 
more favorable opportunities for this drug to act than is the case with 
tetanus. 

This toxin also is ineffective when introduced into the stomach. 
When absorbed into the blood, its effects correspond in general to 
the general effects produced by the bacteria, though in this disease we 



556 ETIOTROPIC PHARMACOLOGICAL AGENTS 

are probably not dealing with a single poison but with a mixture of 
several different ones. They affect primarily the tissues with which 
they first come in contact, and consequently clinically they, as a rule, 
first cause a diphtheritic inflammation of the mucous membranes, with 
the formation of a membrane. When distributed throughout the 
body, these toxins act on many different tissues, as is evidenced by the 
toxic decomposition of the proteids, the alteration of metabolism, and 
the character of the post-mortem findings in different organs, particu- 
larly the hemorrhages and hyperemia of the suprarenals. The lethal 
effects are due chiefly to a typical depression of all the nervous centres. 
In experiments on animals, there are also late developing paralyses of 
the nerves in the neighborhood of the point of infection, which in their 
nature correspond to the postdiphtheritic paralyses observed in man. 

This toxin disappears very rapidly from the blood, for, when it has been 
injected intravenously, blood infused into a second animal exhibits toxic proper- 
ties only if transfused within the first 4-7 minutes. In spite of this, however, 
symptoms of poisoning become manifest only after many hours, even after the 
administration of many times lethal doses. In such case the experimental 
animals lose their power of maintaining their normal positions and become 
paralyzed, while, after a temporary rise, the temperature falls progressively, 
the reflexes disappear, and all functions of the central nervous system fail, 
death occurring as a result of paralysis of the respiration. 

During the development of the poisoning the blood-pressure sinks in a stair- 
like fashion, and the heart, which at the beginning of this fall was still beating 
powerfully, beats more and more weakly, so that after a time cardiac death 
occurs, even if artificial respiration be carried on. It has been shown that these 
effects on the circulation are at the start chiefly due to central vasomotor depres- 
sion, but that in the final stages this is accompanied by a direct toxic action on 
the cardiac muscle. 

It has been shown by Meyer and Ransom that this toxin also may 
reach the centres via the peripheral nerves, for, when injected directly 
into the nerve-trunks, it causes a paralysis of the corresponding cen- 
tres more rapidly and in smaller doses than when injected subcu- 
taneously. Moreover, even if the wound at the point of injection into 
the nerves be bathed with antitoxin, or if large quantities of antitoxin 
be administered intravenously prior to the intraneural injection of the 
toxin, the local paralysis still develops. It consequently is apparent 
that it is quite as difficult for the diphtheria antitoxin as it is for the 
tetanus antitoxin to combine with the toxins, once they have been 
absorbed into the nerves. In any case, even if the antitoxin is able 
to penetrate into the central nervous system, it can render harmless 
such toxin as has already combined with nervous tissues only if it 
follows it there very quickly. Two hours after the injection of toxin 
ten times as large doses of antitoxin are necessary to secure the cura- 
tive effects as are necessary within the first hour (Berghaus, Marx). 

From the above it would appear that the effect of the diphtheria 
serum is due only to its power of protecting against the further absorp- 
tion of new toxin from the points at which it is produced, and not to 
its possessing any true curative action. This is in accordance with the 



DIPHTHERIA ANTITOXIN 557 

clinical experience that, if severe general symptoms of depression of 
the centres, such as are seen in very virulent infections, have already 
developed, these cannot always be caused to disappear by the adminis- 
tration of serum. The often astonishing changes in the symptoms 
which, in less severe infections, usually follow the administration 
of antitoxin, particularly when the serum is used early, may be ex- 
plained on the assumption that new toxin can no longer reach the cen- 
tral nervous system, and that the effects of that which has already 
been combined there can still be overcome by the cells affected. 

However, more recent experiments (F. Meyer) show that it is still pos- 
sible to secure a cure by the intravenous injection of very large doses of serum 
even 6-8 hours after the injection of the toxin, and consequently it is not im- 
possible that the antitoxin by a mass action may attract to itself toxin which 
has already combined with the nervous centres. On the other hand, this is con- 
tradicted by the experience of most observers that the postdiphtheritic paralyses 
are not influenced by the serum treatment. Recently, however, favorable results 
have been claimed from the use of very large doses of serum in cases of post- 
diphtheritic paralysis {Comby). 

It would therefore appear to be certainly proven only that the 
antitoxin protects the nervous system and other cells against further 
absorption of the toxins. Consequently the earliest possible adminis- 
tration of the antitoxin serum is of the utmost importance. Intra- 
venous administration permits the antitoxin to become effective at 
once, but when administered subcutaneously the serum is absorbed 
only very slowly {Morgenroth) . As the intravenous administration 
apparently produces more pronounced side effects than the subcu- 
taneous injection (Tachau), it is perhaps of practical importance that 
the antitoxin is absorbed decidedly more rapidly when injected intra- 
muscularly than when injected subcutaneously {Morgenroth ) . 

The curative effects of antidiphtheritic serum are due to its power 
not only of protecting the nervous system from further absorption 
of the toxins but also of neutralizing them in the tissues where the 
bacilli are multiplying and manufacturing their toxins. These bacilli 
cause their local effects, such as the formation of membranes, with 
the aid of their toxins, which cause the damage to the neighboring 
tissues, as a result of which a favorable culture-medium is prepared 
for the further multiplication of the bacilli. As the antitoxin neutra- 
lizes the toxins in the tissues, the bacilli are deprived of these weapons, 
and in this fashion is explained its favorable action on the local infec- 
tion, which is usually rapidly checked by the serum injection, so that, 
under the influence of the natural curative powers of the body, it 
promptly clears up. This prevention of the multiplication of the 
bacilli and of the manufacture of their toxins, then, secondarily aids 
in bringing about the disappearance of the nervons symptoms, the 
fever, etc., just as is the case when diphtheria is treated locally by 
caustic agents as advised by Locfllcr. 



558 ETIOTROPIC PHARMACOLOGICAL AGENTS 

The strength of the antidiphtheritic serum is, like that of other sera, ex- 
pressed in immunity units, a unit being that amount of serum which in vitro will 
detoxicate for guinea-pigs a certain amount of .standard toxin. According to the 
German Pharmacopoeia, diphtheria serum, which may be preserved by the addi- 
tion of phenol or creosol, must contain at least 300 immunity units per cubic 
centimetre. Sera of high potency contain over 500 such units per cubic centi- 
metre. As a rule, 1000-G000 units should be injected, but in severe cases much 
larger doses should be given. For prophylactic treatment 500 units are, as a 
rule, sufficient. A dried antitoxin is also obtainable, which contains no anti- 
septics and must contain at least 5000 immunity units per gramme. 

BIBLIOGRAPHY 

Berghaus: Zentralbl. f. Bakt., vol. 48, p. 450; vol. 49, p. 281. 

Combv: Arch de med. des enfants, 1904 and 1906. 

Marx': Ztschr. f. Hyg., 1901, vol. 38. 

Meyer, Fritz: Arch. f. exp. Path. u. Pharm., 1909, vol. CO. 

Meyer u. Ransom: Arch, de Pharmacodyn., 1905, vol. 15. 

Morgenroth: Ther. Monatsh., 1909, January. 

Tachau: Ther. der Gegenw., 1910, August. 

BACTERIOLYSINS 
"When, instead of the soluble metabolic products of bacteria, atten- 
uated or killed bacteria are used to produce immunity, the immune 
sera acquire the power of acting specifically on the bacteria in ques- 
tion. In this fashion it is possible to obtain bacteriolytic sera, as was 
first shown by Pfeijfer for the cholera vibriones. 

Guinea-pigs injected with a lethal quantity of these vibriones die with 
symptoms similar to those of the algid stage of cholera, and very active vibriones 
are found in the peripheral cavities. If, however, such animals be injected 
with a sufficient dose of an immune serum obtained from another animal, ren- 
dered immune by the injection of non-lethal doses of these bacteria, they do not 
die, and their peritoneal fluid contains vibriones which are altered in their 
form and in their behavior to staining agents, and it is possible actually to see 
" how their bodies pass into solution in this exudate." 

The mechanism of this phenomenon has been explained by experi- 
ments in vitro {Metschnikoff) as follows : Bacteriolysis occurs in vitro 
only when fresh immune serum is brought in contact with the bacteria, 
while such serum loses its specific powers when kept for a long time 
or when heated to 60° C, but regains it when the fresh serum of 
normal adults is added. This indicates that bacteriolysis results from 
the combined action of two substances, one of which is present in the 
normal serum of non-immunized animals, but is very unstable. On 
the other hand, the specific component of the baeteriolysin, which is 
present only in the serum of the immunized animals, is more stabile 
and resistant to heating. 

Of bactericidal sera we have thus far antistreptococcal, anti- 
meningococcal, antipneumococcal, antityphoid, and anticholeraic sera 
and many others, but their practical value is still sub judice. 

BIBLIOGRAPHY 

Metschnikoff: Ann. de l'lnst. Pasteur, 1895. 

Pfeiffer: Deut. med. Woch., 1894, and Ztschr. f. Hyg., 1894. 



BACTERIOLYSIS AND HEMOLYSIS 559 

HEMOLYSIS 

The studies of bacteriolysis have led to the clearing up of another 
biologically important phenomenon, that of haemolysis. Just as specific 
antigens, the bacteriolysins, are formed in the body after injection 
with the antigens of the bacterial bodies, so also the sera of animals 
injected with other heterologous blood-cells acquire the power of 
acting specifically on and of dissolving these cells. Thus, the injection 
of heterologous blood-cells causes the production of hemolysins. 
For example, if a gminea-pig be injected with a rabbit's blood, its 
serum, which normally does not hernolyze rabbit's blood-cells, becomes 
hemolytic for these cells. Such a hemolytic serum becomes ineffective 
when heated to 55°-60°, but may be reactivated by the addition of 
fresh normal rabbit or guinea-pig serum. As was first recognized 
by Bordet, hemolysis also is due to the combined action of a thermo- 
labile normal constituent of the blood and a thermostable antibody, 
whose formation results from the injection of a heterogeneous blood. 
Normally the serum of many species of animals is hemolytic for cer- 
tain heterologous bloods, so that without any preparatory treatment 
they, hemolyze them. 

Hemolysis results from the hemolysin attracting to itself the anti- 
gen contained in the red cells and thus causing the destruction of their 
structure. It goes without saying that hemolysis may also result from 
pharmacological actions of a very different sort, if only these actions 
are exerted upon integral constituents of the cell body. Examples 
of this are the hemolysis produced by substances which dissolve the 
lipoids which form a portion of the body of the blood-corpuscles, — for 
example, that caused by saponin or by chloroform, ether, etc. The 
hemolysis produced by hypotonic salt solutions, which cause destruc- 
tion of the cells as a result of the inhibition of water, may also be 
mentioned. 

The thermolabile substance present in the serum, the cooperation of which 
is essential for haemolysis, is probably derived from the leucocytes, being either 
secreted by them or set free when they die. Thus far there is no uniformity in 
tin- conceptions of the manner in which these two substances act together in bac- 
teriolysis and haemolysis. According to Bordet's views, both substances act 
directly on the cells, but the substance present in normal serum, named by him 
cytase, can produce lysis only if the specific substance formed during immuni- 
zation, named by him "substance sensibilitrice," has acted on the cells in a 
manner comparable to that in which mordants prepare fabrics for dye-Btuffs. 

Ehrlich, On the other hand, was able to show that the stable specific sub- 
stances, but not the thermolabile ones, the complement, may be made to combine 
with BUSCeptible red cells and thus be removed from the serum. He consequently 
assumes that the substance formed during immunization, named by Pfeiffer the 
immune substance and by EhrKoh amboceptor, combines with the blood-cells but 

by itself cannot produce lysis. It is only when it combines with the complemenl 
that a substance is formed which combines with the cells and dissolves them. 

Mure recently Arrheniua has explained the combined action of these two 
substances on the assumption that the effective compound formed by the immune 
body and the complement is not formed in the serum, or else is not stable there, 
but that it is formed only in the blood cell when both substances are present. 



560 ETIOTROPIC PHARMACOLOGICAL AGENTS 

BIBLIOGRAPHY 

Arrhenius: Ergebn. d. Physiol., 1908, p. 539. 

Bordet: Ann. de FInst. Pasteur, 1895. 

Ehrlich: Gesammelte Abhandlg. z. Immunitatsforschung, Berlin, 1904. 

Sachs: Die Hiiniolysine, Wiesbaden, 1902. 

Agglutinins. — As a general thing antibacterial immune sera pro- 
duce a second specific effect on the corresponding bacteria, which 
consists in agglutinating them. These agglutinins, which were dis- 
covered by Gruber and Durham, are of great practical importance, 
particularly as a means of diagnosing typhoid (Widal reaction). 

BIBLIOGRAPHY 
Gruber u. Durham: Munch, med. Woch., 1896. 

Precipitins. — Another property of many antibacterial immune 
sera is their power of precipitating substances obtained from dead 
bacteria of the species used for immunization (Kraus). The sub- 
stances responsible for this precipitation are known as precipitins, 
and are always formed when heterologous proteid reaches the blood. 
Thus precipitins for serum albumin, lactalbumin, etc., may be formed. 
As sera thus obtained always give the precipitate or cause precipitation 
in the highest dilutions only with the proteid (the precipitinogen) 
used in the preparatory treatment, and as the reaction grows weaker 
the more distant the relationship between the tested proteid and the 
precipitinogen, this biological reaction has acquired great importance 
as the most delicate means of distinguishing between different proteids, 
— for example, in the differentiation between human and animal blood. 

BIBLIOGRAPHY 

Kraus: Wien. klin. Woch., 1897. 

Cytotoxins. — Specific serum may be prepared not only against 
blood-cells and bacteria but also for all possible kinds of cells. Thus, 
by preparatory' treatment with spermatozoa Landsteiner has obtained 
a serum which paralyzes their movements, and v. Dungern a specific 
serum for ciliated epithelium. These cytotoxins are also in a certain 
sense specific, being always most toxic to those cells which were used 
in the preparation of the serum. These investigations are mentioned 
here because it appears entirely possible and probable that cytotoxic 
sera may be used to cause specific destruction of or damage to certain 
cells, as, for example, those of neoplasms. 

BIBLIOGRAPHY 

v. Dungern: Munch, med. Woch., 1899. 
Landsteiner: Zentralbl. f. Bakteriol., 1899. 
Sachs, H.: Biochem. Zentralbl., 1903, vol. 1. 



CHAPTER XVIII 

FACTORS INFLUENCING PHARMACOLOGICAL 
REACTIONS 

Solubility. — The old axiom ' ' Corpora non agunt nisi soluta" should 
be corrected by the addition of ' ' seu solibilia. ' ' For instance, undis- 
solved zinc reacts with sulphuric acid in the presence of water and 
is dissolved in it, but gold, being insoluble, is inactive. This law holds 
true in all pharmacological reactions, and, if a substance or compound 
is completely insoluble in the body, as is the case with barium sulphate, 
or paraffin, it produces no pharmacological effects, but, if it is soluble 
to start with or if it becomes so as a result of interaction with the 
tissues, as is the case with sulphur, it can produce such reactions. 

Most of the chemical antidotes act by transforming the poisons in the stomach 
and intestines into insoluble — or at least poorly and slowly soluble — compounds, 
thus preventing or at least retarding their absorption and their toxic actions. 

Adequate Amount. — While solubility is the first essential for a 
pharmacological effect, the second one is that a sufficient quantity of the 
drug shall come in contact with the tissues or organs on which it exerts 
its actions. 

The receptive organs of the nerves of taste and smell react to immeasurably 
small quantities of active substances, and many other cells act to equally small 
amounts of adequate physiological stimulants. As an example of this the reader 
is reminded of the chemically scarcely recognizable and still efficient epinephrin 
content of the arterial blood. Moreover, certain other substances may, under 
certain conditions, prove toxic in almost immeasurably small amounts, as is the 
case with those minute traces of copper which are present in water distilled 
from a copper vessel, and which exert a harmful action on certain vegetable or 
animal cells introduced therein ( p. 5G3). 

In all of these and in all analogous cases where extremely small quantities 
of drugs exert a physiological activity, it has been possible experimentally to 
determine the lower limits and the conditions for such activity. They have nothing 
whatever to do with the claimed effects of homoeopathic dilutions of drugs. The 
claims made by homoeopathy are based on no experimental tests, but only on 
uncritical and, from their very nature, improbable hypotheses. 

Direct local actions will, it is clear, be influenced by the amount 
applied and, in the case of substances already in solution, the concen- 
trations employed. 

Power of p< m I ml ion into the deeper tissues is also of special im- 
portance for any action elsewhere than on the very surface of the 
body. Caustic substances, which destroy the tissues, penetrate with 
difficulty if they form a firm and insoluble eschar, but more readily 
if the compounds formed are soft or fluid (see Caustics, p. 401). Id 
general, lipoid-soluble substances penetrate more readily than lipoid- 
36 50 1 



562 FACTORS AFFECTING DRUG ACTIONS 

insoluble ones, and of these latter the readily diffusible more readily 
than those which diffuse with difficulty. This last rule, it is clear, 
holds good for the 

Absorption of drugs from the circulating blood by cells lying 
at a distance from the original point of absorption. 

The concentration of a drug in the blood, which determines its 
quantitative distribution in the various cells and organs, depends on 
the relative rapidity of its absorption and of its elimination or destruc- 
tion. A drug reaches the circulation most rapidly and to the full 
amount of the dose administered when it is injected intravenously — 
in the case of gases when it is inhaled — and almost as rapidly when 
injected intramuscularly ; but decidedly more slowly, and almost never 
in its entire amount, when it is injected into the subcutaneous tissues, 
for a portion of it is absorbed and more or less tenaciously retained 
by them. Drugs enter the blood most slowly and least completely 
through, the mucous membranes, and of these the mucous membranes 
of the stomach and of the bladder are almost impermeable for sub- 
stances not soluble in fats. "When absorbed from the intestines, drags 
first pass into the liver, where they meet with a new barrier, many of 
them being transformed chemically by this organ, while others are 
absorbed and retained by it, at any rate for a time. 

If the elimination through the stomach, intestines, or lungs, or if 
the distribution of the drug keep pace with its absorption, its concen- 
tration in the blood can never become high, and in the case of many 
substances, such as curare, if they be administered orally, the concen- 
tration in the blood never attains an adequate or threshold value. 
In case the normal active elimination be pathologically diminished, for 
example by renal insufficiency, it is possible that an unexpectedly high 
concentration of the drug in the blood may be attained so that a 
correspondingly pronounced pharmacological or toxic action results. 

Distribution. — With a certain concentration of the drug in the 
blood, however, it (the drag) is by no means equally distributed 
between all the organs and cells, but, according to their particular 
physical or chemical affinity for the drug, it is absorbed by them in 
different amounts and with varying rapidity. Consequently the final 
distribution of a drug throughout the body depends also on the rate 
at which it enters into the various tissue fluids. If the whole quantity 
enters these at one time, the more avid cell A will, in comparison with 
the less avid cell B, attract to itself relatively more of the drug than 
will be the case when the drag enters these fluids only gradually and 
consequently circulates around in these fluids for a longer time but in 
higher dilution. If J. be not only the more avid but also the specifi- 
cally susceptible cell, and B the less avid and relatively insusceptible 
cell, the pharmacological effect is more pronounced when the whole 
dose is given at once ; but, if the more avid cell be the less susceptible 



SIZE OF DOSE 563 

one, then small, rapidly repeated doses will be the most effective. 
While it is not possible to predict for every drug how it will behave in 
this respect, it is possible to determine this empirically for any given 
one (Beinaschewitz). 

Except in the case of the locally acting caustics and irritants, the 
quantity of the drug which actually acts on the specifically susceptible 
cells, as a rule, forms only an immeasurably small portion of the dose 
administered. After absorption a drug is distributed by the blood 
and lymph throughout the whole body, and, according to its physico- 
chemical properties, is retained and stored up by cells of the most 
different sorts, either mechanically or by capillary adhesion or by 
entering into solution or chemical combination with the cellular con- 
stituents. Cumulation — that is to say, the absorption and retention 
of relatively large amounts of the drug by certain cells and cell com- 
plexes — renders possible the elective action of even extremely small 
doses. For example, 1 mg. of digitoxin distributed throughout a body 
weighing 70 kilos gives a dilution of one to 70 million, a concentration 
which is far from high enough to exert any appreciable action on the 
cardiac muscle, were it not for the fact that this poison is absorbed 
and retained by the cardiac muscle more than by any other cells, and 
consequently may attain in it an adequate concentration, just as copper 
salts in an extremely dilute solution (1 mg. in 100 1.) are absorbed 
and accumulated by alga? in far greater concentration (Devoux). 

BIBLIOGRAPHY. 
Beinaschewitz, F. : Therap. Monatshefte, October, 1910. 
Devoux: Compt. rend. Academie des Sciences, vol. 131, p. 717. 
Straub, W.: Arch, di Fisiol., 1903, vol. 1, p. 55. 

Relationship between the Size of the Dose and the Intensity 
of the Pharmacological Action. — While the absorption and the suf- 
ficient storing up of a drug in certain cells and organs are naturally 
a necessary preliminary condition for its elective pharmacological 
action thereon, it can by no means be used as a measure therefor, for 
many cells may accumulate a substance in considerable amounts with- 
out being harmed or functionally disturbed (Straub). Examples of 
1h is are the intra-vital staining methods used in histology and the 
forensically important accumulation of many poisons in the liver, 
kidney, spinal marrow, etc. 

The amount of the drug which finally becomes effective determines 
the actual degree of the pharmacological action, but this amount and 
the effect produced are by no means directly proportional, for so long 
as it remains below a certain amount, the threshold value, no appre- 
ciable effect at all is produced, for very slight chemical disturbances 
are borne by living cells without appreciable alterations of their func- 
tionx, jusl as they support the daily and hourly variations of osmotic 
tension, of lenipcniture, and of other factors in their normal environ- 



564 FACTORS AFFECTING DRUG ACTIONS 

ment. Consequently the ineffective or just effective doses must be 
subtracted from the different doses administered in order to determine 
the true ratio between them. 

If, as is always necessary in the case of medicinal administration, 
that portion of the drug which is retained in other organs, and which 
does not reach the insusceptible organs at all, be also included in the 
"threshold dose," the difference becomes still greater. 

For example, if for a normal adult the empiric threshold dose of digitoxin 
be about 0.9 mg., — that is, if this be the dose which produces a hardly appreciable 
effect, — the amounts of digitoxin which actually come into action when 1 mg. 
and when 2 mg. are administered may be stated to be in the proportion ( 1.0 minus 
0.9) to (2.0 minus 0.9), i.e., 0.1 to 1.1 = 1 to 11. Consequently, while the pharma- 
cological effect of 1.0 mg. may be just appreciable, the dose of 2.0 mg., which is 
apparently only twice as large, may be unexpectedly severe and perhaps dangerous. 
This example is not a hypothetical one, but is the result of experiments made by 
Koppe on himself. 

Unfortunately, we have no methods by which the intensity of 
pharmacological actions may be directly measured except in the case 
of certain blood poisons, in which the intensity of action may be 
estimated by the extent to which the red cells lose their coloring 
matter.* 

The final amount of haemolysis caused in like suspensions of blood- 
cells by different quantities of a hemolytic agent expresses, in per- 
centages, the functional relationship between the amount of the 
hemolytic agent and the intensity of its action. 

Further, the rapidity with which a certain determinable effect (for 
example, the cessation of respiration in fish or the death of bacteria) 
occurs after a certain dosage may serve as an indirect measure of its 
activity. In such case the degree of activity is the reciprocal of the 
rapidity with which the action is produced. Using such methods, it 
has been shown that, as a rule, the rapidity with which toxic effects 
are produced increases much more rapidly than do the corresponding 
doses, calculated after subtraction of the threshold dose. 

In Fig. G2 the curve represents the intensity of the hemolytic action, and 
in Fig. 63 the unbroken curve represents the time required for the various concen- 
trations of ether to narcotize small fishes, and the broken curve, which is the 
reciprocal of the time curve, represents the intensity of the narcotizing action. 
Both of these curves, the one indicating the percentage of haemoglobin dissolved 

* This method, however, assumes that with partial haemolysis each red 
blood-cell gives up a corresponding portion of its haemoglobin, — that is, is partially 
poisoned. However, up to the present it is uncertain whether this is actually 
the case, or whether in the partial haemolysis of a given number of red cells a 
certain portion of them are completely haemolyzed while the rest retain their 
normal quantity of coloring matter. As a general thing, this last is assumed 
to be the case, although, in view of the regular curves of haemolysis obtained in 
such experiments, this is hard to understand. According to unpiiblished experi- 
ments of Handoicski, partial haemolysis is the expression of the different resisting 
powers of the different blood-corpuscles in a certain quantity of blood, and it 
appears that the youngest blood-cells are the more resistant to haemolytic sera 
and those hemolysins which act on the lipoids. 



SIZE OF DOSE 



565 



out of a given number of erythrocytes by increasing amounts of saponin and 
the other the intensity of the narcotic action of increasing amounts of ether, show 
the rapid augmentation of the toxic action. The efficiency of disinfectants increases 
just as rapidly in proportion to the increase of their concentration, the time 
needed for the killing of bacteria being indirectly proportional to the efficiency 
of different concentrations (Paul, Birstein, u. Reuss). 















r 


|80 










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i 










/ 




£60 










/ 












/ 




t 








/ 






1 














■J 

10 








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8 
















).l c 


z c 


3 C 


.5 C 


.75 





180 



2cm 3 'Ao %oSAPONIN 

to /oaf. cm. 
Blood 



4,3 4.5 4.7 4,9 5.1 5,3 5.5 51% Ether 

Time Curve 

Intensity- (reciprocal of time curve) 

Fig. 62. Fig. 63. 

This means that cells acted upon and to some extent affected by 
a certain amount of a toxic substance, or certain portions of them 
not yet affected and still functioning normally, become less and less 
resistant and more and more susceptible to increasing amounts of the 
same substance, until finally the smallest increase is sufficient to pro- 
duce the maximum effect. This is apparently almost the converse of 
the ratio between the intensity of perception and increasing stimuli 
as expressed in the law of Weber and Fechner. Fig. 64 expresses 
this contrast graphically. 



. 




- 
















: 


/^— 


/' 
























I / 


Strength of 
Stimulus. 







12345 10 15 20 

- Degree of Intensity 

sensibil ity of effect 

Fio. 64. 



In many cases the effect produced by very small doses is the direct 
opposite of that produced by larger ones, the smaller doses stimulating 
certain vital phenomena while larger ones inhibit them, just as moder- 
ate heating stimulates, while overheating first narcotizes and finally 
kills living cells (II. Meyer). In animal pharmacology we meet with 



566 FACTORS AFFECTING DRUG ACTIONS 

this reversal of the effect in the case of the narcotics of the central 
and peripheral nervous system, in connection with many central ex- 
citants, — for example, strychnine, HCN, and ELS, — and with many 
so-called alternatives, — for example, arsenic, phosphorus, etc. Vege- 
table pharmacology also offers many similar examples, — for instance, 
the activity of yeasts may be cpiite generally augmented by minimal 
amounts of different inorganic substances which in large amounts 
depress or paralyze them (Schulz), and the same has long been known 
of the effects of such substances on bacteria and moulds. 

BIBLIOGRAPHY 

Koppe: Arch. f. exp. Path. u. Pharm., 1875, vol. 3, p. 274. 
Meyer, H.: Munch, med. Woch., 1909, No. 31. 
Paul, Birstein u. Reuss: Biochem. Ztschr., 1910, vol. 29, p. 202. 
Schulz: Pfliiger's Arch., 18S8, vol. 42, p. 517. 

Pharmacological Actions Influenced by the Functional Con- 
dition of the Organs. — Another much larger and more important 
group of factors affecting the pharmacological action of various drugs 
and the whole picture produced by them is found in the composition 
and structure and the momentary conditions of those organs and cells 
which are directly acted upon by the drugs in question. In this fashion 
differences, which are otherwise unrecognizable, may betray themselves 
by very striking differences in pharmacological reactions, and these, 
in even the most simple of experiments, may lead to apparently contra- 
dictory results. 

A well-known example of this is the effect of caffeine in frogs, in which 
certain earlier investigators observed only a reflex tetanus similar to that pro- 
duced by strychnine, while others noted only a muscular rigor which was quite 
independent of any action on the spinal cord. Consequently their explanations 
of the actions of caffeine were entirely different. One group of these investi- 
gators, however, had used only Rana esculenta, while the others had used R. tem- 
poraria, and later investigations showed that in these two species of frogs both 
of these pharmacological actions were produced, but that in one species the 
augmentation of reflex excitability and in the other the muscular rigor was 
more readily induced. Consequently, when the pharmacological action developed 
rapidly, only one of these effects was apparent and concealed the other 
(Schmiedeberg). 

Such differences in susceptibility are observed not only between 
the muscles of related or entirely unrelated species, but also between 
the muscles of a single individual. Thus, the more excitable muscles, 
which are more generally active in daily life, react to pharmacological 
agents more rapidly and more decidedly than the more sluggish and 
less used ones. Thus, in birds of flight the leg muscles are less sus- 
ceptible than the much used wing muscles, while the contrary is true 
in those birds which do not fly; and in chronic lead poisoning the 
muscles of the hand and forearm, which are those most used in ordin- 
ary labor, are the first to be affected by paralysis (Teleky). Even 
greater differences in the effect of drugs may be observed in muscles 



CONDITION OF THE ORGANS 567 

with, normal tone and those in which the tone is pathologically aug- 
mented or depressed. Thus, the gravid uterus, whose muscle-fibres 
are more stretched than those of the non-gravid organ and which conse- 
quently are more susceptible to contractile stimuli, ordinarily contract 
when the mixed hypogastric nerve, which contains both exciting and 
inhibitory fibres, is stimulated, while the opposite effect is produced 
in the non-gravid organ. Pilocarpine and epinephrin, like the electric 
stimulation of this nerve, in the one condition cause the uterus to con- 
tract and in the other to relax (Cushny) . What has been stated above 
for the muscle-cells holds good also for all the other cells of the 
organism. 

Generally one may assume that all living cells will show the thus 
far inexplicable tendency to maintain a normal functional mean of 
activity or position, and that they will of their own accord return to 
it if forced to depart from this mean in one direction or the other. 
It is this self -regulating inherited tendency of cells which is responsible 
for the permanence of the individual and of the species, and which is 
the essential cause of the vis medicatrix naturae A very simple and 
at the same time characteristic and instructive example of this is the 
behavior of the tissue cells in the presence of changing osmotic ten- 
sion. If the surviving liver be transfused with hypotonic saline solu- 
tion, it swells up slowly as a result of the swelling of the individual 
cells, but if an isotonic solution be then transfused it rapidly regains 
its normal size and condition. In a similar fashion, under the in- 
fluence of hypertonic solutions, it shrinks but slowly, and regains its 
normal condition very rapidly when isotonic solutions are transfused 
(Demoor) . 

It would thus appear that in living cells osmotic reactions back 
toward the normal are much more readily induced than those in the 
opposite direction. Much the same holds good for the varying con- 
ditions of tension in contractile elements, the state of excitation or 
tone of nerve centres, etc. In this connection the reader is reminded 
of the powerful action of the antipyretics on the pathologically excited 
heat centres (p. 466), and of the power of digitalis to regulate the 
irregularly beating heart (p. 296). 

It must not be forgotten, however, that in the case of -many 
organs and functions the conditions are not so simple as in the above- 
mentioned examples; for normally most of these are continually under 
the influence of a double antagonistic innervation, through which they 
receive both exciting and inhibiting stimuli, either through nervous 
stimulation or the action of chemical substances, such as the hor- 
mones. Thus, the intestinal musculature receives exciting impulses 
through flie vagus and inhibiting ones through the sympathetic; conse- 
quently, it' Hie intestine be completely relaxed, solely because it is 
receiving no exciting stimuli through the vagus, any agent which 
stimulates the vagus produces a marked effect upon it and readily 



568 FACTORS AFFECTING DRUG ACTIONS 

causes a contraction and to a greater degree than if the intestine had 
originally been in a state of moderate contraction. On the other 
hand, if the original relaxation had been due to powerful inhibition 
through the sympathetic, this would oppose the action of the agent 
exciting the vagus, and consequently the effect would be slighter than 
if the intestine had been in a state of ordinary repose. 

BIBLIOGRAPHY 

Cushnv: Journ. of Physiol.. 1910, vol. 41, p. 235. 
Demoor: Bull, de l'Ac. r. de Big., December, 190G. 
Schmiedeberg, J.: Arch. f. exp. Path. u. Pharm., 1873, vol. 2. 
Teleky: Deut. Ztschr. f. Xervenheilk., 1909, vol. 37, p. 284. 

Antagonism. — This physiologically antagonistic nervous mechan- 
ism of all the vegetative organs, the unstriped muscles, the glands, 
and the circulatory organs, must consequently often modify the 
actions of those drugs which act on this system, and be the cause and 
the explanation of the reciprocal antagonism between those pharma- 
cological agents which excite the activity of the two portions of this 
antagonistic nervous mechanism. 

The antagonistic effects of small and large doses of the same drug may also 
depend on this physiologically antagonistic innervation. Thus, according to 
Schwartz, small doses of choline excite the inhibiting centres for the pancreatic 
secretion, while large doses stimulate the secretory nervous organs lying in the 
gland itself. Wertheimer and Lepage state that just the opposite is true for 
atropine. 

Little is actually known, and still less is understood, of the antag- 
onistic effects produced in the various organs by the internal secre- 
tions, which may be looked upon as physiologically formed pharmaco- 
logical agents. Among these mention may be made of the partial 
antagonism between choline and epinephrin (see pp. 164, 188, 189) . In 
other cases, such as that of the probably antagonistic action of epi- 
nephrin and the pancreas hormone on the liver-cells (see pp. 171, 419), 
we are entirely in the dark as to how they act, nor can this antag- 
onism be explained in the above-mentioned manner. When we en- 
deavor to explain the antagonistic actions of the thyroid hormones and 
those of the hypophysis and of the reproductive glands, we are still 
more at a loss. 

There is no particular difficulty in understanding the antagonism 
between various drugs and poisons when this depends on the antago- 
nistic innervation of certain organs. Thus, if a drug stimulates the 
vasodilators it is clear that it must oppose the action of another which 
stimulates the vasoconstrictors. 

Much more difficult to understand, however, is an antagonism in 
which one drug overcomes the effect produced by another one in the 
same cell or functional element without the aid of any antagonistic 
physiological mechanism. Here it is necessary to differentiate between 



DISTOXICATION AND ANTAGONISM 569 

two fundamentally different methods by which, such results may be 
obtained, — namely, by distoxication and by true physiological antag- 
onism. 

(a) Distoxication. — When one substance chemically changes or 
combines with another,- — that is, satisfies its specifically active affinity, 
— it appears to act antagonistically. Such an action we speak of as a 
chemical distoxication, examples of which are the distoxication of 
cyanides and of nitrils by hyposulphites. 

Hydrocyanic acid and the nitrils, for example malonitril, are readily trans- 
formed by active sulphur into the less toxic sulphocyanides, and consequently 
it is possible, by subcutaneous or, better, by intravenous injection of a solution 
of hyposulphite, to rescue animals which have received lethal doses of a cyanide 
or a nitril and which are already in the death struggle. On account of the extra- 
ordinary rapidity with which the respiratory centre is paralyzed in cyanide 
poisoning, the antidote in such cases must immediately follow the poison, or 
artificial respiration must be performed for some minutes, in order to overcome 
the effects of this toxic action. As the nitrils produce their effects much more 
slowly, their distoxication can be accomplished after the lapse of a considerably 
longer period. 

In this case the antidote penetrates into the already poisoned cells or into 
their immediate neighborhood, and destroys the poison absorbed by them, a fact 
which is of decisive importance for its efficiency. 

Examples of distoxication as a result of chemical combination are 
furnished by the distoxication of free acids by alkaline carbonates, that 
of oxalates by lime salts (Januschke) , and that of the saponins (Ran- 
som) and of the crotalus toxin (Fuhner) by cholesterin. 

When the combination formed by the poison and the protoplasm, 
or more correctly the reacting constituent thereof, is reversible with 
difficulty or not at all (for instance, on account of its complete insolu- 
bility), it is quite clear that even an adequate antidote, which is able 
to combine with the poison, cannot reverse the toxic reaction. How- 
ever, in such case it may be possible to repair the protoplasm by 
replacing such of its constituents as have combined with the toxic 
agent. This is actually what occurs in the antagonistic action of lime 
salts in oxalate poisoning. When, on the other hand, the toxic reac- 
tion is readily reversible, as for example in chloral or chloroform poi- 
soning, a substance which possesses an avidity for the toxic substance 
equal to or greater than that of the cell constituents can attract the 
toxic substance to itself and thus overcome the poisoning of the cell. 
Thus, according to NcrJcincj, it is possible to lessen or overcome a 
deep chloroform narcosis by the intravenous injection of a lecithin 
emulsion. 

(b) True Antagonism. — The antagonism between atropine and 
muscarine is the classic example of true physiological antagonism, 
for these two antagonistically acting drugs have no chemical affinities 
for and do not react with each other, but produce directly opposite 
effects upon the same organic elements. 

Nasse's studies of the action of poisons on ferments have given 



570 FACTORS AFFECTING DRUG ACTIONS 

us a knowledge of the simplest type of this kind of antagonism. He 
found that the activity of the yeast ferment, invertin, was inhibited 
by KC1 and accelerated by NH 4 C1, and that in certain relative pro- 
portions these two substances could overcome each other's actions; 
and that the same was true for the alkaloids quinine and curarin, the 
first inhibiting, the latter favoring, and the two together, if in proper 
proportions, leaving unaltered the activity of this ferment. In other 
words, he found that there was a complete reciprocal antagonism be- 
tween these substances. Inasmuch as neither potassium chloride nor 
curare enters into any chemical reaction with ammonium chloride and 
quinine respectively, we are able to understand their reciprocal antag- 
onism only if we assume the existence in the ferment of a common 
point of attack for both of the antagonists, which is influenced in 
opposite directions when it combines with one or the other of these. 

A somewhat rough comparison may aid in elucidating this. Sea 
water possesses a certain conductivity or, in a physiological sense, ex- 
citability, which may be increased by the addition of alum or mark- 
edly decreased by that of alcohol, for the former is an electrolyte and 
the latter a non-conductor. Either of these may be removed from the 
water by the addition of the other, for the alum can be precipitated 
by the addition of alcohol and conversely the alcohol may be separated 
from the water by the addition of alum. Consequently, according to 
the varying proportions of these two substances added, an equilibrium 
may be established in the sea water with increased, diminished, or unal- 
tered conductivity. An example of a similar phenomenon closely re- 
sembling certain vital phenomena is furnished by the action of saline 
solutions on colloids, the salts of monovalent and bivalent metals 
inhibiting each other's power of precipitating proteid and, according 
to their effective amounts, forcing each other out of their sphere of 
activity. An entirely similar antagonism between the monovalent 
and polyvalent metallic ions has been demonstrated in connection with 
the action of saline solutions on living organisms, such as fundulus 
eggs, and muscles and contractile organs generally.* 

These facts compel us to assume for the antagonists in question 
a similar reversible reaction, — that is, a labile combination of some sort 
or other with the common substratum of the living cells, in which, 
according to the preponderance of one or the other of the antagonists, 
inhibition or excitation of the cell function is more strongly developed. 
For such a hypothetical phenomenon there actually exists an exactly 
investigated example in the behavior of oxygen and carbon monoxide 
in the red cells. Here oxygen is the stimulating or exciting agent and 
carbon monoxide the inhibiting or depressing one, and, while they do 
not react with each other, they both possess a similar but quantita- 

* Tn this connection special mention should be made of the reciprocal 
antagonism between K and Na ions, which, so long as their relative proportion 
be about 1 to 17, are non-toxic to the fundulus, but which, if this relative proportion 
be altered appreciably, no longer compensate each other and become toxic (Loeb). 



ANTAGONISM 571 

tively very different affinity for haemoglobin, and consequently, accord- 
ing to the relative amounts present, are able to force each other out of 
their combinations with haemoglobin. It is for this reason that it 
is possible, by supplying oxygen freely, to restore to a normal con- 
dition blood which is actually saturated with carbon monoxide, pro- 
vided only that the poisoning has not already persisted so long as to 
bring about the death of the erythrocytes. Under such conditions, 
however, the removal of the carbon monoxide takes place slowly and 
with difficulty, for its affinity to haemoglobin is 200 times as great as 
that of oxygen, and consequently the feeble affinity of the oxygen mole- 
cules must be compensated for by their number, — that is, by a larger 
amount and higher concentration. For this reason inhalation of oxy- 
gen can by no means always rescue the victims of coal gas poisoning, 
for the removal of the carbon monoxide requires so long a time that 
in the interim the brain and the heart may succumb to asphyxia. 

In the above we have touched on a question of fundamental im- 
portance, the question as to the possibility of an absolute reciprocal 
antagonism. This possibility has been repeatedly denied on the 
ground that, while it is possible to bring about paralysis in a stimu- 
lated organism, it is not possble to bring about stimulation in a 
paralyzed one, and that the paralyzing poison under all conditions 
will maintain the upper hand. In a static sense this is correct; but 
the static condition in a cell poisoning holds good only for the irre- 
versible toxic actions of colloids, toxins, and certain metallic ions, 
while in almost all other acute poisonings the combination between 
poison and protoplasm is a dissoluble one, so that the cell may be 
restored again and the poison washed out from it if it be bathed 
with blood which has been freed of the poison. If then the indifferent 
pure blood be replaced by one containing an antagonistic drug, — that 
is, one possessing a similar affinity for the affected elements of the 
cells, — the original poison must be forced out from its combinations 
and the distoxication be accelerated, while at the same time the stimu- 
lating antagonistic effect of the antidote will produce its action. 

A very instructive example of such an antagonistic rivalry between 
two substances is furnished by the effect of lime salts in combating 
the narcotic effects of magnesium salts (Meltzer and Auer) (see p. 
110). In a more general form this reciprocal antagonism between 
the four cations Ca', Mg', Na', and K' is more or less clearly evidenced 
in living organisms, for the tissues apparently can maintain their nor- 
mal functions, particularly their normal excitability, only when these 
cations are present in the tissues in their correct relative proportions} 
(Loeb, Meltzer). It is probable, also, that the fact that the previously 
mentioned toxicity for low forms of life, exhibited by the minute 
amounts of copper present in distilled water, may be abolished by the 
addition of a small amount of NaCl, is to be explained in a similar 
fashion (Birflot, Loeb). 



572 FACTORS AFFECTING DRUG ACTIONS 

The reciprocal antagonism between atropine and pilocarpine and 
muscarine is also to be attributed to similar factors. Here, too, the 
affinity of one of the toxic agents for the cell protoplasm and perhaps 
also its power of penetrating into it is greater than that of the other, 
just as is the case with carbon monoxide and oxygen, and consequently 
the antagonistic effect may be looked upon as dependent on the rela- 
tive toxic affinities and the effective quantities and the rates of reac- 
tions of the different drugs. 

In this view of these phenomena it is assumed that the antagonistic 
drugs possess a common — that is, exactly the same — seat of action in 
the organs; but, as a matter of fact, this is absolutely incapable of 
experimental proof, and can be logically deduced only in those cases, 
where strict reciprocal antagonism has been demonstrated. However, 
there is another possible explanation for such antagonism, — namely, 
that the paralyzing drug acts on the cells at a less peripheral point 
than does the stimulating one. In such case, on the one hand, the 
paralyzing drug would block the path for the stimuli arriving through 
the nerves to such a degree that these stimuli would no longer reach, 
the more peripheral elements with sufficient strength to produce exci- 
tation, while, on the other hand, as the stimulating drug renders these 
last-mentioned elements more excitable, it would in turn be able to 
render them susceptible to previously ineffective stimuli. If the de- 
pression or paralysis — that is, the blocking — is so complete that abso- 
lutely no stimulating impulses can pass, the stimulating antagonist 
is ineffective, and consequently in such case one may in a strict sense 
speak only of a one-sided or pseudo antagonism. This would appear 
to be the case, for example, with the antagonism between curare and 
physostigmine, and it is probable that the antagonism between cerebral 
and spinal stimulants and depressants rests upon a similar basis. 
For example, morphine narcosis may be partially counteracted by 
atropine, and atropine excitation by morphine. A similar partial an- 
tagonism exists between such narcotic drugs as chloral hydrate and 
alcohol, and such stimulating ones as caffeine, strychnine, and cocaine. 

Probably in all these eases we are never dealing with a complete paralysis 
but only with a great weakening or obstruction of the conduction of excitation, 
so that the normal impulses are weakened or retarded on their way to the motor 
ganglion-cells and consequently are unable to produce in them the essential 
discharge of nervous energy. The antagonistic stimulating drug may then pos- 
sibly so lower the threshold for stimuli in the motor neuron or in the interposed 
switching stations that the abnormally weakened centripetal stimuli are suffi- 
cient to bring about the necessary discharge of energy. This conception is sup- 
ported by the fact that the receptive organs of the spinal reflex arc are always 
more rapidly and markedly affected by narcotic drugs than are the motor ones, 
so that the latter may still retain an almost normal excitability and yet remain 
at rest because they do not receive adequate stimuli from the inhibited receptive 
tracts. 

BIBLIOGRAPHY 
Baum, H.: Diss., Rostock, 1892. 

Bullot: Univ. of Calif. Publ. Phvsiol., 1904, vol. 1, p. 199. 
Fiihner: Arch. f. exp. Path. u. Pharm., 1910, vol. 63, p. 383. 



IMMUNITY 573 

Januschke: Arch. f. exp. Path. u. Pharm., 1909, vol. 61, p. 363. 

Loeb, J.: Dynamik d. Lebenserscheinungen, Leipzig, 1906. 

Loeb, J.: Biochem. Ztschr., 1911, vol. 31, p. 450. 

Metzer and Auer: Am. Journ. of Physiol., 190S, vol. 21, p. 400. 

Nerking: Munch, med. Woch., 1909, vol. 29. 

Bansom: Deut. med. Woch., 1901, No. 13. 

Schwartz: Zentralbl. f. Physiol., vol. 23. 

Wertheimer et Lepage: Compt. rend, de la Soc. de Biol., 1901, p. 759. 

Immunity. — Many forms of immunity are based upon chemical 
distoxication, this being particularly true for immunity to toxins 
(see p. 547), for ; as previously stated (p. 552), the antitoxins, which 
have been formed in the body, circulate about in the blood and capture, 
as it were, the toxins which may enter it. 

Apparently the antitoxins penetrate only with difficulty or not at all into 
the pericellular lymph-spaces or the cells themselves, for, if a toxin without enter- 
ing the circulation be brought in contact with the susceptible cells, it produces 
its typical effects upon them even in immunized animals whose blood is full of 
antitoxin (Meyer, Hume, Ransom, Gley) . Many other poorly diffusing bodies 
behave in a similar fashion. For example, sodium ferrocyanide solution may be 
injected into the blood without producing any notable effect, but, if the spinal 
cord itself has been injured by a small puncture, or cut so that the poisoned 
cerebrospinal fluid can penetrate to it, violent symptoms of poisoning immediately 
appear. 

Immunit}^ to toxins is consequently practically a humoral one, and, 
with the exception of congenital insusceptibility, thus far it has not 
been possible to demonstrate or produce a cellular immunity * except 
in the case of the immunity of the red cells to eel serum (Tschisto- 
witsch). 

On the other hand, immunity to all other poisons is almost always 
cellular, whether it be a natural one or one acquired by habituation. 

The immunity of the rabbit to atropine appears to form an exception to 
the rule, for, according to Fleischmann, the serum of rabbits possesses the power 
of destroying atropine, a property not possessed by the blood of goitrous rabbits, 
which are quite susceptible to atropine (Cloetta). 

Salamanders are very insusceptible to curare, and it has been claimed thai 
this immunity can be transferred to other animals by the injection of sala- 
mander blood, but Heuser was unable to confirm this. 

In many cases we to a certain extent understand the chemical 
agencies with which the cells render poisons harmless or with which 
they defend themselves. Thus, the liver-cells neutralize acids with 
ammonia, which otherwise would be synthetized into urea, and distoxi- 
cate numerous poisons by conjugating them with glycuronic and 
sulphuric acids or by oxidizing or reducing them. These chemical 
powers of the cells may be very decidedly augmented by exercise; 
for example, by the administration of increasing doses it is possible 
to increase the power of conjugating camphor with .ulyeuronic acid 
(Schmiedclx rn u. Mri/cr) or the power of destroying morphine 

* Genetically, immunity to toxins is. however, cellular, for the antitoxins 
are reaction products and cast-off portions of celK 



574 PHARMACOLOGICAL REACTION FACTORS 

(Faust). By gradually storing up calcium and transforming the 
soluble fluoride into the insoluble calcium fluoride, yeast cells can 
accustom themselves to a concentration of ammonium fluoride which 
at the start would have been very poisonous (E front). 

In other cases this chemical cellular immunity has not yet been 
completely explained. For example, in the above-mentioned habitua- 
tion to morphine, the insusceptibility of the cerebral cells, which 
apparently take no part in the destruction of the morphine (Riibsa- 
men) and which in spite of this become very insusceptible to this drug, 
is entirely unexplained, as is also the relative immunity of the mor- 
phinist to cocaine (Chouppe). Equally unexplained is the great 
natural immunity of the hedgehog, chicken, and frog to cantharidin, 
and that of the cardiac muscle of the toad to digitalis-like substances. 
Surprising but still capable of explanation is the immunity of certain 
moulds (Penic. glaucum, etc.), which can live in solutions containing 
from 1 to 2 per cent, of CuS0 4 , while others (for example, Muc. 
mucedo) are killed by 0.016 per cent, of this salt, and alga? even 
by 1 in a billion. In this case the immunity is due to the impermeabil- 
ity of the cell wall of the Penic. glaucum for this salt. [This mould 
shows the same insusceptibility to Zn and to Hg salts (Pulst).] 

On the other hand, it goes without saying that toxic substances 
cannot produce their specific effects in organisms in which the corre- 
sponding susceptible organs are either not at all or not sufficiently 
developed. In animals which have no vomiting centre apomorphine 
cannot produce emesis, and strychnine cannot cause reflex convulsions 
in foetuses and new-born animals, in which the spinal cord is not yet 
completely developed (Gusserow) . 

Moreover, Avhen the later effects of a toxicological action, such as 
the secondarily caused death, are alone noted and used as the criterion 
and measure of immunity, paradoxical results are obtained. In such 
case frogs would appear very immune to curare, because paralysis of 
the respiration does not kill them so long as their skin is exposed to 
the air; and mice would appear relatively immune to CO, for in the 
presence of a low external temperature they are able to withstand 
otherwise rapidly fatal amounts of this gas because they cool off 
rapidly to the surrounding temperature and, like hibernating animals, 
so lessen their metabolism that they are able to get along with the 
small amount of oxygen which is still brought to them by the haemo- 
globin (Bock). Further, the foetus in utero supports without direct 
damage long-continued morphine or chloroform poisoning, because it 
does not use its own respiratory organs, but, when it is born and be- 
comes dependent on its own respiration, it is extremely readily killed 
by the smallest quantities of morphine or chloroform. This is the 
explanation of the fact that a deep morphine or chloroform narcosis, 
induced in the mother a short time before or during the birth, imperils 
the life of the child, although this is not the case during the pregnancy. 



FACTORS AFFECTING DRUG ACTIONS 575 

BIBLIOGRAPHY 

Bock, Job.: Exp. Unders. over kulilte intox., Kopenhagen, 1895. 

Chouppe: Compt. rend. Soc. Biol., 1889. 

Cloetta: Arch. f. exp. Path. u. Pharm., 1911, vol. 03, p. 427. 

Effront: cited from Ergebn. d. Physiol., 1907, vol. 6, p. 71. 

Faust: Arch f. exp. Path. u. Pharm., 1908, vol. 44, p. 217. 

rieischmann: Arch. f. exp. Path. u. Pharm., 1911, vol. 62, p. 518. 

Gley: Compt. rend. Ac. Sc, November, 1904. 

Gusserow: Arch. f. Gym, 1871, vol. 3, p. 241; vol. 13, p. 03. 

Heuser: Arch, intern, de pharm., 1902, vol. 9. 

Clever and Ransom: Arch. f. exp. Path. u. Pharm. 

Pulst: Ergebn. d. Physiol., 1907, vol. 6, p. 75. 

Pulst: Jahrb. f. -wissensehaftl. Botanik, vol. 37, p. 205. 

Riibsamen : Arch. f. exp. Path. u. Pharm., 1908, vol. 59, p. 227. 

Schmiedeberg u. Meyer: Ztschr. f. physiol. Chemie, 1879, vol. 3, p. 422. 

Tschistowiteh : Ann. de l'lnst. Pasteur, 1S99, vol. 13, p. 406. 

Synergism. — If the -weakening or prevention of the action of one 
drug by that of another be called antagonism, the one-sided or recipro- 
cal augmentation of such action may be termed synergism (Filhner). 
As this phase of pharmacology has thus far been the subject of com- 
paratively few exact investigations, our knowledge of it is relatively 
slight. 

An increased carbon-dioxide tension in the blood (diminution of 
the alkaline carbonates in acid intoxication) favors the toxic action 
of the chlorates on the red blood-cells, perhaps because of an increased 
liberation of free chloric acid. Another example is furnished by the 
combined effects of cocaine and epinephrin, Frohlich and Loeivi hav- 
ing found that doses of cocaine which by themselves produce no appre- 
ciable effects very markedly increase the effects of epinephrin on the 
blood-vessels, the muscles of the bladder, the dilator of the iris, etc. 
In this case the effects cannot be considered as due to a simple summa- 
tion of similar pharmacological actions, for they are altogether too 
great. At present no satisfactory explanation for the above can be 
given, and for the present we must satisfy ourselves with merely 
stating that the cocaine produces a sensibilization comparable to the 
sensibilization of light-sensitive substances or to the action of the 
mordants in dyeing. 

Of much greater practical importance is the synergism of the 
narcotics, — for example, the combined effects of scopolamine and mor- 
phine (see p. 7f)), of morphine and ether or nitrous oxide, of scopo- 
lamine and uivthane, of magnesium sulphate and chloroform (Mclt- 
zer, Biir(ji). A similar, or rather an analogous, phenomenon is the 
very powerful action exerted on the heat-regulating centre by combina- 
tions of certain convulsant poisons and hypnotics (see p. 473). 

Such augmentation of pharmacological actions may be determined 
quantitatively with greater exactness with combinations of hsemolytic 
substances. .Mixtures of hemolytic sera or mixtures of other indiffer- 
en1 hemolytic agents — Eor example, mixtures of saponin and ammonia 



576 SYNERGISM 

— produce a much greater amount of haemolysis than would correspond 
to the effects of the separate hemolytic agents (Cernovodeanu, 
Arrhenius). 

In all these cases we are dealing with the combined action of 
pharmacologically dissimilar substances, for pharmacologically sim- 
ilar substances simply produce the summation of their separate 
actions. 

While Honigmann's experiments with mixed narcosis with ether and chloro- 
form or ether and alcohol apparently indicate a potentiation, Biirgi and Madelon 
have not been able to confirm his results in experiments which are free from 
sources of error. However, theoretically such a potentiation could be possible, 
for Fiihner has shown that the solubility of chloroform in water is diminished 
by the addition of ether, and consequently the distribution coefficient of such a 
mixture between water and oil (see p. 105) is altered in such a fashion as to favor 
an augmentation of its narcotic effects. However, this alteration is so slight 
in those solutions of the narcotics which actually are formed in the body during 
anaesthesia, that they are practically of no significance. 

It consequently appears as if the function of cells is more markedly 
and more readily influenced when a smaller number of different con- 
stituents of their protoplasm is acted upon chemically or physically 
than is the case when a larger number of similar constituents are thus 
acted upon. 

Apparently the same holds true for the action of toxic substances 
on lower organisms. Lepine has recommended for parenchymatous 
disinfection a mixture of several antiseptics in such extreme dilution 
that no harmful effect either on the tissues treated or on the pathogenic 
bacteria could be expected. The mixture of these different antiseptics, 
however, proved to be very efficient antiseptically, but completely 
harmless for the host, because the larger number of the ingredients 
were by themselves hardly toxic at all. If the dilutions employed 
by Lepine are noted, it is apparent that the antiseptic effect of the 
whole mixture cannot be explained as the result of simple addition. 
However, systematic investigations of such potentialized effects of 
antiseptic mixture have not yet been conducted.* 

More recently such combination methods have been employed by 
Ehrlich in the treatment of trypanosome diseases, he having found that 
the combination of less active trypan dyes with other less toxic basic 
dyes formed very effective mixtures, and having obtained similar 
results with the proper combination of different arsenic compounds. 

It may be that the same principle lies at the bottom of the favor- 
able therapeutic effects which the older medicine often endeavored to 
obtain by the use of mixtures of different drugs. In this connection 
mention may be made of the practical value of combinations of 
cathartics. The old experience that opium is distinctly more efficient 
in quieting the intestine and relieving colic than is accounted for 

* Tlie synergism of phenol and the cresols and solutions of salts rests upon 
a quite different basis, being explainable physically (see p. 504). 



HYPERSUSCEPTIBILITY 577 

by the morphine contained in it, may be explained as resulting from 
the synergistic action of its various alkaloids. 

BIBLIOGRAPHY 
Arrhenius: Communicat. de 1'Inst. Seroth. de l'etat danois, 1908, vol. 2. 
Biirgi: Deut. med. Woch., 1910, Nos. 1 and 2. 
Cernovodeanu, Henri: Conipt. rend. Soc. Biol., 1905. 
Cernovodeanu, Henri: Compt. rend. Ac. Sc, 1905. 
Ehrlich, Paul: Berl. klin. Woch., 1907, Xos. 9-12. 
Frohlich u. Loewi: Arch. f. exp. Path. u. Pharrn., 1910, vol. 62. 
Fuhner: Miinch. med. Woch., 1910, 1911, p. 179. 
Honigmann: Arch. f. klin. Chirurgie, 1899, vol. 58. 
Lepine: Rev. de med., 1886, p. 184. 

Madelung: Arch. f. exp. Path. u. Pharm., 1910, vol. 62, p. 409. 
Meltzer: Berl. klin. Woch., 1906, No. 3. 
Rotter: Zbl. f. Chir., 1888. 

Hypersusceptibility. — While in the preceding paragraphs it has 
been possible to explain at least a portion of the various insuscepti- 
bilities as the result of antagonism, — or, more correctly expressed, as 
the result of the fact that certain chemical substances combine with or 
destroy each other, — on the other hand, it appears that the explanation 
for certain types of hypersusceptibility or idiosyncrasy is to be found 
in the synergistic action of two or more substances. Thus, in accord- 
ance with certain observations previously noted, it may be possible to 
explain the extreme susceptibility of certain individuals to cocaine 
as due to the fact that in these individuals there is from the start an 
exaggerated tone of the sympathetic system, which is constantly kept 
in a state of excitation by epinephrin, so that even the slightest aug- 
mentation of this tone produces exaggerated effects. 

In a similar fashion Eppinger and Hess attribute abnormal susceptibility 
to pilocarpine to an abnormally high vagus tone, which in turn is attributed by 
them to the action of a vagotonic hormone. 

Frohlich and Chiari have shown that the excitability of the vege- 
tative nervous system and of the cerebrospinal nerve-endings is mark- 
edly augmented by dhninishing the lime content of the body, sub- 
stances administered to an animal or formed in its own metabolism 
which deprive the body of lime — e.g., oxalic acid — rendering it abnor- 
mal ly susceptible to drugs exerting such pharmacological actions. The 
same seems also to hold good for many phlogogenetic substances, for, 
according to Chiari and Januschke, the degree in which the vessels 
become permeable and in which transudations occur is dependent on 
the lime content of the tissues, its augmentation hindering the forma- 
tion of transudates and oedema while its diminution increases these. 
The reaction of the skin to phlogogenetic stimuli is also dependent in 
Hie same way upon its lime content (see p. 495). 

Calcium is, however, not the only constituent of protoplasm I lie 

varying amount of which determines or influences its momentary 

power of reacting to drugs and poisons, bu1 is only a better known 

and more thoroughly investigated example of the importance of the 

37 



578 FACTORS AFFECTING DRUG ACTIONS 

composition of the tissue fluids, and one which renders it probable that 
the remarkable susceptibility of many individuals to certain sub- 
stances, such as morphine, strawberries, shell-fish, etc., is dependent 
on a peculiar chemical composition of the tissue fluids and proto- 
plasm.* The old name idiosyncrasy, meaning peculiar mixture, would 
therefore appear based upon a fundamentally correct idea. 

The nature of certain other kinds of hypersusceptibility is still 
entirely inexplicable, this being particularly the case with acquired 
cellular hypersusceptibility to certain toxins. If an animal receive 
small doses of tetanus toxin, which produce almost imperceptible or no 
toxic effects, its central nervous system becomes hypersusceptible to 
this toxin, so that amounts thereof which ordinarily would have no 
effect cause the development of severe tetanus (v. Bchring). 

This hypersusceptibility of the nervous system may be readily demonstrated 
by the injection of tetanus toxin into the nerve-trunks or the central nervous 
system of immunized animals, whose blood and other body fluids contain tetanus 
antitoxin (Meyer a. Ransom). It manifests itself even more clearly in animals 
which have been inoculated intraneurally with a dose of tetanus large enough 
to cause only a slight local tetanus. In such animals no antitoxin is formed, but, 
on the contrary, after the lapse of 2 or 3 weeks an extreme hypersusceptibility 
develops, so that a severe general tetanus results from the subcutaneous injection 
of amounts of the toxin which ordinarily would produce no tetanus (Loewi u. 
Meyer). 

This might all be looked upon as due to the summation of the 
action of the two doses were it not for the paradoxical fact that two 
or more very small doses, injected into the spinal cord at long intervals, 
produce much greater toxic effects than a many times larger dose 
injected at one time. This might be explained on the assumption, that, 
when one large dose of the toxin is administered, those tissues which 
are not specifically susceptible — the connective tissues, etc. — absorb 
the toxin relatively more rapidly or in larger amounts, in comparison 
with the nervous protoplasm, than is the case when a small dose is 
administered, in which latter case the nerves would absorb relatively 
more of the toxin ; in other words, on the assumption that the distribu- 
tion of the toxin to the different tissues varies greatly with its varying 
concentration. In a previous section (p. 562) a similar behavior of 
pharmacological agents has already been instanced. Otherwise there 
remains only the assumption that the first subliminal poisoning has 
gradually produced a persistent alteration of the condition of the 
spinal cord, as a result of which its power of reacting to this toxin 
has been very gradually augmented, — in other words, the assumption 
of a sensibilization, a true cellular hypersusceptibility. 

A certain analogy for this is furnished by the so-called autocatalytic reac- 
tions. Catalyzers are substances which accelerate or facilitate certain chemical 

* In this connection see Reid Hunt, The Effects of a Restricted Diet and of 
Various Diets on the Resistance of Animals to Certain Poisons, Hyg. Labor. Bull. 
No. 69, Washington, June, 1910. 



ANAPHYLAXIS 579 

reactions. Now, there are certain chemical reactions in which a catalyzer is 
produced, which accelerates this very same reaction, so that, when it has once 
started, it progresses with steadily increasing rapidity and intensity, the elements 
which react with each other being sensibilized to each other. Numerous biochemi- 
cal processes exhibit this progressive character [Robertson). 

Behring and Eitashima have apparently shown that something' of 
the same kind occurs in rabbits, repeatedly slightly poisoned with 
diphtheria toxin, in whom hardly any antitoxin is formed. 

BIBLIOGRAPHY 
Behring: Allgem. Ther. d. Infektionskrankh., 1899. 
Behring u. Kitashima: Berl. klin. Woch., 1901, p. 157. 
Chiari u. Frohlieh: Arch. f. exp. Path. u. Pharm., 1911, vol. 64, p. 369. 
Chiari u. Januschke: Arch. f. exp. Path. u. Pharm., 1911, vol. 65, p. 120. 
Eppinger u. Hess: Die Vagotonic, Berlin, 1910. 
Loewi u. Meyer: Arch. f. exp. Path. u. Pharm., 1908. 
Alever u. Ransom: Arch. f. exp. Path. u. Pharm., 1903, vol. 43, p. 369. 
Robertson, Br.: The Monist, 1910, p. 368. 

Anaphylaxis. — Another type of hypersnsceptibility, named by 
Richet "anaphylaxis" (ana — without, phylos — weapon), appears to 
be of an entirely different nature. 

If a foreign proteid substance, either toxic or non-toxic, be subcu- 
taneously or intravenously administered to an animal, after a lapse 
of some weeks the intravenous injection of a very small amount of this 
same substance (and this substance only) causes a very rapid, severe, 
and often fatal poisoning, which in its character is always the same no 
matter what kind of proteid has been used to sensitize the auimal. 
The symptoms produced vary, however, with the species of auimal 
used, being in the case of dogs those of vascular paralysis, vomiting, 
purging, dyspnoea, general muscular weakness, and unconsciousness, 
while in the rabbit they are chiefly due to a peripherally induced 
spasm of the bronchial muscles which mechanically prevents respira- 
tion. Witte's peptone, when injected intravenously, produces the 
same symptoms in these animals (Biedl u. Kraus) , so that it may be 
concluded that the anaphylaxis poison is identical with or similar to 
some substance present in this mixture. 

It would appear that, as a result of the first injection of the anti- 
gen, the organism gradually manufactures a specific antibody which, 
when it again comes into contact with the antigen, forms a substance 
which is acted upon and decomposed by a peptic ferment present in 
the blood-plasma, with the formation of the anaphylactic poison which 
causes the anaphylactic shock. Inasmuch as, if the animal survives 
this shock, he is immune to this antigen, it would seem that the anti- 
body or the hypothetical ferment in the blood has been entirely con- 
sumed in the first anaphylactic reaction. This antibody persists in 
the blood for a long time, sometimes for many years, and may be 
transferred to normal individuals if they be transfused with such a 



580 FACTORS AFFECTING DRUG ACTIONS 

serum, so that they also react to the antigen in question with an acute 
anaphylactic shock.* 

In man such anaphylaxis has been observed particularly in indi- 
viduals treated with various antitoxic sera, the symptoms consisting of 
exanthematous eruptions, oedema, fever, general malaise, and collapse. 
Similar symptoms also occur in specifically susceptible individuals 
after eating certain foods, among others egg albumen, and in this 
case, too, the symptoms are to be attributed to an anaphylactic pre- 
disposition acquired in some fashion or other (Bruck, Klausner). 
Thus far we have been unable to gain any further insight into the 
nature of these remarkable phenomena, and still less explained is the 
hypersusceptibility of the tissues observed in repeated infection with 
hay-fever toxin, tuberculin, vaccine, and other bacterial toxins {von 
Pirquet) . This is also the case with idiosyncrasies to certain chemical 
well-defined substances, among which special mention should be made 
of iodoform and antipyrine, which in predisposed individuals regularly 
cause exanthemata and oedema, with fever, dyspnoea, and pronounced 
lassitude. B ruck's experiments have shown that this predisposition 
may be induced in animals by the injection of the blood-serum of 
predisposed individuals, and consequently it too appears to be of an 
anaphylactic nature (Klausner) . Bruck explains it as follows: Under 
the chemical influence of these substances a heterologous proteid is 
formed in the body which acts as an antigen, and when, following 
the renewed ingestion of the drug, this is again formed, it excites the 
anaphylactic attack. 

BIBLIOGRAPHY 
Anderson and Frost: Hyg. Labor Bull., No. 44, Washington, 1910. 
Biedl u. Kraus: Wien. klin. Woch., 1009. No. 1. 

Biedl. u. Kraus: Handb. d. Tech. u. Method, d. Immunitatsforsehung, Jena, 1910. 
Bruck, C: Berl. klin. Woch., 1910, Nos. 12 and 42. 

Friedberger, E.: Ztschr. f. Immunitatsforsehung u. exp. Ther., 1909-11, vols. 3-4. 
Friedberger, E.: Berl. klin. Woch., 1910, No. 50. 
Klausner: Munch, med. Woch., 1911, Nos. 3, 27 and 28. 
Pfeiffer: Problem d. Anaphylaxie, Jena, 1910. 

v. Pirquet: Allergie. Ergebn. d. inn. Med. u. Kinderheilk., 190S, vol. 1, p. 420. 
Richet:-Frav. du lab. de phys., 1909, vol. G. 
Fuchet: Journal medical franc, Sept. 15, 1910. 

In the discussion of various pharmacological actions, reference has 
repeatedly been made to the fact that pathological conditions produce 
alterations in the functions and reactions of the various organs and 
thus provide altered conditions for pharmacological actions. Our 
knowledge of pharmacological actions under such conditions must in 
many cases be based solely upon clinical experience and observation, 
for, with the exception of certain experimental infections, it is but sel- 
dom possible in the laboratory experimentally to produce and analyze 
disturbances similar to those occurring in human disease. Wherever 

* For literature see Anderson and Frost, Biedl. u. Kraus, Pfeiffer, Fried- 
berger. 



RATIONALISM VS. EMPIRICISM 581 

it has been possible to do this experimentally, pharmacologists have 
been able to amplify the fundamental knowledge obtained by experi- 
ments on normal animals by that obtained in diseased ones and to 
note the differences in such actions as observed under pathological 
conditions. This has been especially the case in the investigation of 
the antipyretics and of those drugs influencing the circulation, the 
respiration, the formation of blood, the metabolism, and the processes 
of inflammation. Such experimental therapy has thus been able to 
give the explanation for, and the theoretical foundation of, not only 
etiotropie treatment, but also for the symptomatic treatment of many 
pathological conditions. 

However, in so far as it- is not a question of purely etiotropie phar- 
macological actions, it is always' the analytical experiment on normal 
animals or organs which forms the actual foundation for our phar- 
macological knowledge and the deductions drawn therefrom. Conse- 
quently, it is entirely correct to question whether, and how far, 
these deductions hold true for pharmacology in its connection with 
normal, and particularly in connection with diseased, human beings. 

Although, with the exception of the cerebrum and the skin, human 
organs and their reactions do not differ essentially from those of other 
mammals, and consequently pharmacological laws discovered by ex- 
periments on animals may in principle be applied to man, still there 
are sufficient, although not always clearly understood, reasons why the 
phenomena observed in pharmacological experiments on animals do 
not always agree entirely with the therapeutic effects as observed at 
the bedside. As a matter of fact, it is the outspoken or quietly cher- 
ished opinion of many physicians that the effects of drugs in human 
patients can in no way be reconciled with those observed in animal 
experiments, and that the latter are, generally speaking, of no value 
for practical therapeutics, in which experience by the bedside should 
be the sole guide for the physician. 

On the surface this view appears to be correct, for there is no 
doubt that with the aid of such experiences the physician may be a 
successful therapeutist, just as an experienced peasant may be a good 
farmer. It would be unfortunate if neither the cultivation of the 
ground nor the treatment of the sick were possible without theoretical 
understanding, for this is neither desired nor possessed by every one. 
It is also not to be questioned that the practically experienced man 
possessing no theory would, for the time at least, be a more useful 
farmer or physician than the theoretical individual who possesses no 
practical experience. Advances, however (for example, in agricul- 
ture the employment of artificial fertilizing agents), are only very 
exceptionally made without the aid of theoretical knowledge, and for 
this reason alone, not to speak of others, theoretical knowledge is abso- 
lutely indispensable for practical therapeutics. Every apparently 
erroneous dictum of pharmacology is probably capable of sooner or 



582 FACTORS AFFECTING DRUG ACTIONS 

later being explained, and if theory is to become a guide for practice 
it must never disregard those practical experiences which rest on a 
firm foundation. As a matter of fact, there can be absolutely no 
contradiction between correct theory and correctly interpreted prac- 
tical experience. Actually the often proclaimed contradiction between 
pharmacological theory and clinical experience, as between theory 
and practice in any case, is due to nothing else than the fact that, 
from premises gained by experiments, incorrect or too far-reaching 
deductions are drawn and built up to form an incorrect theory. The 
apparent discrepancies between theory and practice will always show 
themselves wherever the adequate and necessary conditions of the 
experiment are very numerous and only to be learned and controlled 
gradually. This must be the case particularly often in medicinal 
therapy, where in most cases the effects observed will not be solely 
the direct pharmacological action of the drug, but will be the result 
of many complicating factors. 

For example, in the intestine the effect of the pharmacological action of 
opium may express itself in an evacuation of the bowels after a constipation 
lasting for many days, or, conversely, by a constipation after a diarrhoea lasting 
an equal time (see p. 192) ; or in the kidneys, according to circumstances, the 
pharmacological action of pilocarpine may result in augmentation or diminu- 
tion of the kidney secretion (see p. 375). 

It is consequently necessarily futile, and therefore unjustifiable, 
to demand that from pharmacological experiments alone one should 
deduce and predict the successful action of a drug in each separate 
pathological condition, for this is just as impossible as it would be 
to foresee the whole clinical symptom complex, which will result in 
any given case from a certainly known cause of disease, such as an 
infection with typhoid; for here, too, in different cases, different 
secondary conditions result from the primary disturbance, which are 
dependent on various fortuitous conditions, just as is the case with 
the symptoms resulting from a pharmacological action. In order 
to foresee with a certain exactness those symptoms on which will de- 
pend the therapeutic effects, it would be necessary that one could 
correctly judge of the condition of all the organs of the body which 
may be of importance in a given case. Just here it is that the phy- 
sician 's art, and his intuition, which has been ripened by experience, 
should play its part in combination with his theoretical knowledge. 



INDEX 



Abortifacients, 223, 224. (See also 
Uterine movements, drugs influenc- 
ing) 
Abrin, eye action in, 160 

phlogogenic action, 483, 490 
Absorption from blood by cells, 562 
by intestine, 173, 174 
by stomach, 172, 173 
Accelerator, actions (see under Circu- 
lation) 

AcETANILIDE, 478 
ACETARSANILATE, 535 
AcETARSANILIC ACID, 535 
ACETPHENETIDIN, 478 

Acetyl-salicylic acid, antipyretic ac- 
tion of, 472 
excretion and fate, 472 
therapeutic actions, 4S0. (See 
also under Salicylic Acid and 
Salicylates) 
Acid, acetic, as counterirritant, 487 
boric, as antiseptic, 509 
toxicity of, 508, 509 
carbolic (see Phenol) 
chromic, as caustic, 491 
formic, as counterirritant, 487 
hydrochloric, biliary secretion, ac- 
tion on, 170 
secretin secretions, 168 
secretion, drugs acting on, 166, 

167 
stomach movements, action on, 
186 
hydrocyanic, action on blood, 450 
lactic, as caustic, 491 
nitric, as caustic, 491 
phosphoric, elimination by intes- 
tine, 172 
picric, astringent action, 493 
pyrogallic (see pyrogallol) 
salicylic (see Salicylic acid) 
sulphurous, as disinfectant, 506 
tannic (see Tannin) 
trichloracetic, as caustic, 491 
Acidosis, 421 

central nervous system, effects on, 
394 
Acids, antagonism to alkalies, 569 
autolysis, action on, 393 
blood reaction, action on, 393 
caustic action, 491 
disinfectant power, 503 
factors influencing disinfectant pow- 
der, 503 
gastric secretion, action of, on, 165 
local actions, 394, 491 
metabolism, action on, 393-395 
mineral, as disinfectants, 506 



Acids, vegetable, action on blood, 449 
Aconite, 109 

antipyretic action of, 466 
local action, 109 
toxic action, 110 
Aconitine (see Aconite) 
Actol, 513 

Adequate quantities, 561 
Adonidin, 302 

Adrenaline (see Epinephrin) 
Agaricin, antisudorific action, 376 
Agaricus muscarius, 24S 
Agglutinins, 549, 560 
Airol, 520 

Alcohol, 43 ff. (See also Alcohol and 
Alcohol, ethyl) 
in acidosis, 50, 433 
amyl, elimination in bile, 170 
in angina pectoris, 326 
antidote to phenol, 516 
antiseptic action, 47, 507, 508 
circulation, action, 48, 25S, 274, 316, 

324 
circulatorv failure, in treatment of, 

316, 324 
as counterirritant, 486 
depressing action on nervous system, 

48 
in diabetes, 433 
diaphoretic action of, 371 
ethyl, cause of toxic amblyopia, 

144 
euphonic action, 47 
fate in body, 49 
fats, as sparer of, 432 
as food, 431-433 
for muscles, 430 
value, 50 
gastric secretion, action on, 167 
habituation to, 46 
heart, action on, 258, 259 
infections, influence on, 49 
intracranial pressure, action on, 48 
kidney, action on, 359 
methyl, muscle function, action on, 
430 
toxic amblyopia, from, 144 
motor function, action on, 45 
muscle function, action on, 429-431 
perception, action on, 47 
proteid, as sparer of, 432 
respiration, action on, 46, 47, 334, 

335, 337 
"stimulating" action, 46 
stomach absorption, effect on, 173, 

346 
temperature regulation, action on, 
49, 455, 473 

5S3 



584 



INDEX 



Alcohol, vasoconstriction, action on, 
326 
vessels, action on, 48, 274 
Alcohol group, 43 ff. 

antipyretic action of, 473 
diuretic action, 359 
hemolytic action, 452 
respiratory sedative action of, 
337 
Alkalies, antagonism to acids, 569 

blood-reaction, action on, 391, 392 
bronchial mucous secretion, action 

on, 343 
in diabetes, action sugar excretion, 

418 
disinfectant power of, 503 
excretion of, 390 

gastric secretion, action of, on, 165 
gout, action in, 390, 391 
intestinal glands, action on, 172 
local actions, 392 
metabolism, action on, 389-392 
renal stone, action on, 390 
respiratory centre, action on, 333 
skin, action on, 487 
stomach, action in, 165, 393 
uric acid, action on, 390, 391, 421 
urine, action on, 368, 391 
urolytic action of, 391 
Alkaloids eliminated by intestine, 172 
general characteristics of, 22 
narcotic, mode of action, 108 
Allergy, 546 
Aloes, 208 

abortifacient action of, 208, 223 
bile secretion, action on, 208 
Aloin, kidney, action on, 208. (See also 

Aloes) 
Altitude, high, action on blood, 444 ff. 
metabolism, influence on, 404, 405 
Alum, astringent action of, 216 
Aluminum acetate, antiseptic action, 514 

salts in inflammation, 495 
Alypin, 133, 134 
Amanita muscaria, 248 
Amblyopia, toxic, due to various drugs, 

144 
Ammonia, anaesthetic action, 120 
as counterirritant, 487 
local action, 487 
respiration, action on, 336 
Ammonium bases, chemistry and phar- 
macology of, 8 
salts, diaphoretic action, 372 
expectorant action of, 343 
Amyl chloride, 278 
nitrite (see Nitrites) 

in angina pectoris, 327 
coronary arteries, action on, 289 
heart, action on, 277 
toxic effects, 278 
vasodilator action, central, 276, 
278 
peripheral, 277, 288 



Amylene chloral, 93 

hydrate, 94 
Anaphylactic fever, 462 
Anaphylaxis, 579 
from drugs, 580 
from food, 580 
from sera, 579 
from toxins, 580 
Anaesthesia, circular, 129 
general, 50-83 

accidents in, 58, 68 
apparatus for, 75 
clinical picture, 56 
combined, 78 

synergism in, 78, 79, 82, 
576 
deglution, effect on, 176 
reflexes during, 59. (See also an- 
aesthetics) 
infiltration, 120, 128 
local, 117-135 
by cold, 118 
by compression, 118 
by local ansemia, 118 
morphine-scopolamine, 79 
nitrous oxide, 73 
regional, 123-129 
terminal, 117 
an^esthesin, 132, 134 

antiphlogistic action, 493 
Anaesthetic methods, 75 ff. 
An^esthetica dolorosa, 120 
Anaesthetics, general, 50 ff. 

absorption and distribution of, 

68 ff., 75 
circulation, action on, 63, 68 
haemolytic action of, 452 
history of, 51 
mortality from, 76 
motor function, action on, 57 
nerve trunks in periphery, 

action on, 58 
reflex effects, 60 ff . 
respiration, action on, 59 ff. 
sensory functions, action on, 57 
inhalation, 50 

local, antiphlogistic action of, 482 
Angina pectoris, 327 ff., 330 
Aniline, antipyretic action of, 462, 473 
blood action on, 451 
constitution, 478 
derivatives, 478 
Anisotonic solutions, local effect of, 

120 
Antagonism, 568 ff . 

absolute reciprocal, 571 

by distoxication, 569 

between alcohol group and caffeine, 

strychnine, and cocaine, 572 
between atropine and chloral, 336 
and choline, 248 
and muscarine, 249, 569, 572 
and physostigmine, 152, 572 
and pilocarpine, 373, 572 



INDEX 



585 



Antagonism between calcium and mag- 
nesium, 110, 571 
and muscarine, 249 
choline and epinephrin, 164, 188, 

189, 568 
curare and physostigmine, 9, 152, 

572 
epinephrin and calcium, 463 

and choline, 164, 188, 189, 568 
and pancreas, 171, 419, 568 
KC1 and XH4CI, 570 
magnesium and calcium, 110, 571 
morphine and atropine, 34, 36, 336, 

572 
Na and K ions, 570 
2 and CO, 570 
quinine and curarin, 570 
various salts and metals, 570 
true, 569 
Antagonistic innervation, 567 
Anthelmintics, 521-524 
Anthraquinone derivatives, 207 
Anthrasol, in skin diseases, 518 
Antiarin, 302 
Antibodies, 549 
Anti-emetics, 178 
Antifebrin (see Acetanilide) 
Antiferments, 547 
Antigens, 549 

Antimonial compounds in trypanoso- 
miasis, 536 
Antimony, capillary dilator action, 289 
as caustic, 492 
circulation, action on, 415 
elimination by intestine, 172 
metabolism, action on, 414 
and potassium tartrate, emetic ac- 
tion of, 183 > 
expectorant action of, 184, 344 
systemic actions of, 1S4 
toxic actions of, 183 
Antiphlogistic agents, 481 
analgesic, 492, 493 _ 
Antipyretics, analgesic actions of, 475 
blood, action on, 451 
centrally acting, 468 ff. 
cerebral arteries, action on, 475 
diaphoretic action, 374 
in fever, 464 ff. 

from puncture, 463, 464 
in headaches. 475 
hypnotic actions, 475 
respiration, action on, 333 
as sedatives to heat regulating 

centres, 161-466 
therapeutic uses of, 473 ff. 
vessels, action on, 276 
Antu'vkim: in fever from puncture, 464 
idiosyncrasy to, 580 
group, 477 IT. 

antipyretic effects, 468 ff. 
blood-pressure, action on, 469 
brain, action on vessels of, 326 
metabolism, action on, 468, 469 



Antipyrine group, vasodilating action 

of, 326, 468, 469 
Antiseptics, 497-520 
aromatic, 514-518 
bile, action on, 170 
eye, action on, 160 
general, bacterial factors affecting 
resistance to, 49S-500 
mode of action, 498-503 
spores, action on, 499, 500 
influence of dissociability of, 
501-504 
of lipoid solubility of, 500, 

501 
of neutral salts on, 503, 504 
of surrounding media on, 
504, 505 
methods of investigating, 497, 49S 
urinary, 367, 36S 
Antisudorifics, 375, 376 
Antitoxic sera, 551 
Antitoxins, 543 ff . 
formation of, 549 
limitations of, 552 
in milk, 552 

nature and properties, 547, 548 
specificity of, 548 
Anuria, reflex, 358 

influence of narcotics on, 359 
Ape NT a water, 197 
Aphrodisiacs, 219 

Apo-atropine, as contamination of 
scopolamine, 29 
test for, 29 
Apomorphine, emetic action of, 179 
expectorant action, 343 
muscles, action on, 427 
respiration, action on, 335 
systemic actions, ISO 
Arbutin, 367 
Areca nut, 523 
Arecolin, anthelmintic action, 523 

miotic and mydriatic action of, 153 
sweat glands, action on, 372 
Argentamine, 514 
Argenti nitras (see Silver nitrate) 
Argonin, 514 
Argyria, 217, 514 
Aristochin, 476 
Aristol, 520 
Arnica, 487 

Aromatic substances, fate in body, 514 
Arsacetin, 535, 536 
Absenic, bacteria, action on, 411 
blood, action on, 410, 433 
bone, action on, 410 
capillary dilator action, 2S9, 411 
as caustic, 492 
central nervous syslcin, loxir adion 

on, 412 
circulation, action on, ll l 
eaters, 409, 414 
elimination by intestine, 172 
excretion and fate in body, 1 13 



586 



INDEX 



Arsenic group, 404 ff. 

infusoria, action on, 410 
intestine, toxic action on, 411, 412 
local uses, 413 

and mercury in syphilis, 538-539 
metabolism, action on, 408 ff. 
mode of action of, 409 
muscular paralysis from, 427 
neuritis from, 412 

organic compounds, in protozoal 
diseases, 531 ff. 
specific effects of, 409 
pathological tissues, action on, 411 
plants, action on, 409, 411 
poisoning, acute, 411 

chronic, 412 
presence in living cells, 409 
in syphilis, 536 
therapeutic actions, 412, 413 
tolerance to, 409, 413, 414 
toxicology, 410-412 
in trypanosomiasis, 531 ff. 
yeasts, action on, 409, 411 
Arseniuretted hydrogen, haemolytic 

action of, 409, 452 
Arsenophenylglycin, 536 
Arsonium bases, 8 
Aspidii, oleoresina, 521, 522 

active principles of, 522 
toxicology, 522 
Aspidosamine, emetic action, 180 
Aspidospermine, respiration, stimulant 

action on, 335 
Aspirin (see Acetyl-salicylic acid) 
Asthma, bronchial, treatment of, 345 
iodine in treatment of, 347, 398 
cigarettes, etc., 345, 346 
Astringents, alimentary canal, action 
in, 212 
antiphlogistic actions of, 493-495 
as antisudorifics, 376 
caustic action of, 213 
eye, action in, 160 
obstipating action of, 212 
vessels, action on, 213 
Atophan, purine metabolism, action on, 
421 
uric acid excretion, effects on, 368 
Atoxyl, 534 ff. 

constitution, 535 
derivatives, 534-536 
difference from inorganic arsenic, 409 
optic neuritis from, 534 
in syphilis, 537 
in toxicology, 534 
in trypanosomiasis, 534 
Atropine, antagonism to chloral, 336 

to morphine on respiration, 34, 

36, 336, 572 
to muscarine in heart, 249, 250, 

569, 571 
to physostigmine, 152, 572 
to pilocarpine in sweat glands, 
373, 572 



Atropine, asthma, action in, 345 

Auerbach's plexus, action on, 190 
autonomic nervous system, action 

on, 142 
biliary secretion, action on, 169 
and carbohydrate tolerance, 418 
central nervous system, action on, 27 
in chloroform death, 68 
circulation, action on, 250 
in collapse, 25 
in constipation, 192 
constitution, 154 
convulsant action of, 24 
deglutition, effect on, 176 
in diabetes, 418 
in emesis due to morphine, 33 

to pyloric spasm, 185 
eye, action of on, 153 ff 
gastric secretion, action of, on, 166 
heart, action on, 249 ff. 
hyperchloridia action in, 167 
icterus, action in, 253 
idiosyncrasy to, 156 
immunity of rabbit to, 573 
intestinal motor function, action on, 

190, 191, 192 
intra-ocular tension, action on, 155 
lead colic, in, 192 
metabolism, action on, 382 
in morphine poisoning, 36 
mydriatic action of, 154 ff. 
occurrence, 153 
ophthalmology, uses in, 155 
pancreatic secretion, action of, on, 

168, 568 
poisoning, acute, 156 

acute, treatment of, 156 
chronic, 156 
pyrogenic action of, 462 
respiration, stimulating action on, 

335, 336 
salivary secretion, 164 
secretions, action on, 155 
stomach movements, action on, 166, 
188 
secretion, action on, 166 
substitutes for, 157 
systemic actions, 155 
sweat secretion, action on, 375 
therapeutic uses, 156 
uterine contractions, action on, 222 
-methylium bromide, 418 
Auerbach's plexus, action of drugs on, 
190 ff. 

AURICULO- VENTRICULAR TRACT, digi- 
talis's action on, 266-267 
Autolysis, thyroid substances, influ- 
ence on, 395 
Autonomic drugs, intestinal motor func- 
tion, action on, 190 
stomach movements, action on, 

187 
uterine movements, action on, 
222 



INDEX 



587 



Autonomic nervous system, anatomy and 
physiology of, 136-138 
antagonism between sympa- 
thetic nervous system and, 
140 
atropine, action of, on, 142 
choline, action of, on, 142 
muscarine, action of, on, 142 
physostigmine, action of, on, 
142 

Bactericidal sera, 558 
Bacteriolysins, 550, 558 
Balsam of Peru, 518 
Barium, intestinal motor function, action 
on, 191 
poisoning, sulphates in, 201 
Baths, cold, antipyretic action of, 467 
carbon dioxide, 486 
salt, 488 
sea, 488 
Belladonna (see Atropine) 
Benzoates, biliary secretion, action on, 

170 
Benzol, leucocytes, action on, 447 
Beta-eucaine (see Eucaine B) 
Beta-imidazolylethylamine, 226, 228 
Betaine in ergot, 225 
Beta-naphthol as intestinal antiseptic, 
521 
in skin diseases, 518 
Betel nut, 523 

Bile acids, heart, depressant action on, 
253 
elimination by, 170 
salts, biliary secretion, action on, 170 
secretion of, antiseptics, action on, 
170 
atropine, action on, 169 
benzoates, action on, 170 
bile salts, action on, 170 
calomel, action on, 170 
cathartics, action on, 170 
hydrochloric acid, action on, 

170 
oleates, action on, 170 
pilocarpine, action on, 169 
salicylates, action on, 170 
saline cathartics, action on, 170 
soda, action on, 170 
Bismuth elimination by intestine, 172 
gastric secretion, action of, on, 167 
poisoning, 494 
salts, in inflammation, 494 
subgallate, 216 
subnitrate, absorption of, 215 

mucous membranes, action on, 

215 
nitrite poisoning from, 216 
subsalicylate, 216 
Bittekk, leucocytes, action on, 447 

stomach absorption, effect on, 173 
movements, effect on, 187 
Blood, alkalinity of, 389, 391, 392, 449 



Blood, coagulability of, substances affect- 
ing, 447 

concentration of, agents influencing, 
436 

condensation of, 435 

pharmacology of, 435-452 

plasma, chemical composition of, 
drugs altering, 449 

poisons, 449-452 

pressure (see under Circulation) 

reaction of, 389, 391, 392 

toxicology of, 449-452 

viscosity of, drugs affecting, 448 
Borax, as antiseptic, 509 

as preservative, 509 
Bornyval, 115 
Bread, gastric secretion, action of, on, 

165 
Bromdiethylacetamide (see Neuronal) 
Bromeigon, 115 

Bromides, central nervous system, ac- 
tion on, 111 

epilepsy, action in, 112 

excretion in saliva, 165 
in urine, 113 

metabolism, action on, 387 

organic, 115 

retention in body, 112 
Bromipin, 115 
Bromism, 114 
Bromocoll, 115 
Bromural, 97 

Bronchial spasm, drugs relieving, 345 ff . 
Brucine, action of, 21 

source of, 12 

Cacodylic acid, 533 

difference from inorganic arse- 
nic, 409 
Caffeine (see also Caffeine group) 

accelerator, peripheral, action on, 

252 
antagonism to narcotics, 25 
beverages, 25, 314 
cerebrum, action on, 26 

actions on vessels of, 289, 330 
circulatory action, 313 ff., 360, 361 
in collapse, 25 
constitution, 360 
coronary vessels, action on, 2S9, 

313, 330 
derivatives, muscle and kidney, 

action on, 364 
and digitalis, compared, 267 
diuretic action, 360 ff. 
extra-systoles, power of causing, 268 
fate in body, 315 
fatigue, action in, 429 
general actions, 363 
glycosuria from, 419 
heart action on, 267, 268 
intracranial vessels, action on, 330 
kidney, effect on blood flow through, 

362 



588 



INDEX 



Caffeine, kidney, excretion by, 362 
harmlessness to, 364 
metabolism, effect on, 379 
morphine poisoning, action in, 36 
muscle, action on, 428 
occurrence of, 314 
pulse-rate, effect on, 26S 
respiration, action on, 335, 347 
-sodium benzoate, subcutaneous use 
of, 313 
salicylate, subcutaneous use of, 
313 
temperature, action on, 314, 462 
toxicology, 26, 314 
in treatment of vascular depression, 

312 ff. 
vasoconstrictor centres, action on, 

274 
vessels, action on, 274, 330 

dilator action on, cerebral, cor- 
onary and renal, 289 
renal, action on, 330, 362 
group (see also Caffeine) 
constitution, 360 
diuretic action, 360 ff . 
vasoconstriction in treatment 
of, 330, 331 
Calcium, antagonism in heart between 
muscarine and, 249 
between magnesium and, 110, 
571 
antiphlogistic action, 495, 496 
elimination by intestine, 172 
and epinephrin, antagonistic effects 

on fever, 463 
ions, action on muscles, 422 
precipitants, action on muscles, 422 

cathartic action, 198 
toxic action of, 496 
vegetative system and, 577 
chloride, remote astringent effects, 

495 
hydroxide, alimentary canal, action 

in, 217 
salts, astringent effects, 217, 495 
in inflammation, 495 
leucocytes, action on, 447 
sulphide, depilating action, 210 
Calomel, absorption of, 203 

biliary secretion, action on, 170, 204 

cathartic action, 203 

diuretic action of, 204, 356 

as intestinal antiseptic, 201, 204, 521 

iodides, poisonous interaction with, 

204 
kidney action on, 204 
in syphilis, 541, 542 
toxic action, 204 
Camphor, cardiac failure, in treatment 
of, 310, 316 
central nervous system, action on, 

24, 26 
convulsant action, 24 
in collapse, 25 



Camphor, "curare" action in frog, 8 

as counterirritant, diuretic, action, 

372, 488 
excretion and fate in body, 310, 420 
fibrillation, action in, 256, 257, 316 
heart, action on, 255-257, 310, 316 
in chloralized, 255, 256 
in muscarinized, 255 
in morphine poisoning, 36 
respiratory centre, action on, 335 
reviving action of, 25 
sweat secretion, action on, 372 
systemic actions, 310 
temperature, action on, 473 
therapeutic uses, 310, 316 
vascular depression, in treatment of, 

315 
vasoconstrictor centres, action on, 
274 
Camphoric acid, antisudorific action of, 
376 
a respiratory sedative, 340 
Cannabis indica, 41 
Cantharidin, 489, 490 

aphrodisiac action, 219 
immunity to, 483 
kidney action on, 359, 490 
poisoning, 490 

alkalies in, 490 
therapeutic employment of, 490 
Carbolic acid (see Phenol) 
Carbon dioxide baths, 486 

central nervous system, action 

on, 394 
narcotic action, cause of, 108 
retina, action on, 144 
role in physiology of cells, 395 
stomach absorption, effect on, 

173 
stomach movements, effect on, 

186 
respiration, action on, 332, 333, 

337 
viscosity of blood, effect on, 449 
disulphide, causing toxic amblyopia, 

144 
monoxide, antagonism to 2 , 571 
blood action on, 450 
glycosuria, 419 
poisoning, 450, 571 
Carbonic acid (see Carbon dioxide) 
Cardol, 490 
Carlsbad salts, 202 
Carminatives, 210 
Carniferrin, 442 
Cascara sagrada, 208 
Cassia angustifolia, 207 
Castor oil (see Olium ricini) 
Cathartics, 193-210 

biliary secretion, action on, 170 

classification of, 196 

diuretic action of, 358 _ 

drastic, eliminated by intestine, 172 

large intestine, acting on, 207 ff. 



INDEX 



589 



Cathartics, mode of action of, 195 
saline, 196-203 

alkali loss resulting from, 200 
absorption, action on, 196 
antiseptic (intestinal) effect of, 

200 
biliary secretion, action on, 170 
blood, effect on, 199 
calcium precipitation by, 198 
concentration, influence of, 198 
food, effect on utilization of, 200 
liver, effects on, 201 
metabolism, action on, 388 
systemic actions, 197 
small intestine, acting on, 205 ff. 
Caustic alkalies, local actions, 491 
Caustics, 491 ff. 
Central depressants, 110 

nervous system, pharmacology of, 
11-116 
Cerebral depressants, 27 ff. 
stimulants, 24 

therapeutic indications for, 25 
Chamomile, carminative action, 210 
Charcoal, alimentary canal, action in, 
212 
poisons, power of absorbing, 212 
Chemical constitution and pharmaco- 
logical action, relation between, 98 ff. 
Chloralamide, 934 
Chloral hydrate, 88-92 
acute poisoning, 91 
antagonism to atropine, 336 
as anti-emetic, 185, 186 
antipyretic action, 473 
asthma, action in, 345 
chronic poisoning, 92 
circulation, action on, 90, 253, 

254, 276 
fate in body, 89 
general action, 88 
habituation to, 91 
harmful actions, 90 
heart, depressant action on, 90, 

253-254, 309 
idiosyncrasies to, 90 
local action, 88 
pupil, action on, 136 
respiration, action on, 91, 336, 

338 
therapeutic employment, 90 
toxicology, 91 
vessels, action on ; 90, 276 
cerebral, action on, 325 
cutaneous, action on, 325, 
-326 
Chlorates, blood, action on, 451 
disinfectant, action on, 511, 512 
poisoning by / 512 
Chlorine, as disinfectant, 505, 506 

local irritant action of, 506 
Chloroform, 55 ff. 

anaesthesia, after effects, 74 
asthma, action in, '■', \7> 



Chloroform, blood cells, action on, 56 
blood-pressure, action on, 62 
cardiac death from, 64-66 
a cardiac poison, 63 
chemistry, 55 

circulation, action on, 60 ff . 
concentration in air inspired, 70, 72, 
73 
in blood, 69, 71 
toxic to heart, 63, 64 
as counterirritant, 486 
death from, 63-67 

analysis of causes of, 66 
in man, 66-68 
distribution in ana?sthesia, 103 
excretion and fate in body, 55 
general action, 55 
heart, action on, 62, 63 

depressant action on, 253 
kidneys, action on, 74 
local action, 55 
percentage in blood, 69 
respiration, action on, 59 
retina, action on, 144 
synergism with ether, etc., 78, 575, 
576 
with magnesium sulphate, 575 
temperature, with ether, 473 
toxic action, 56 

late, 74 
vasodilating action, central, 62 
vasodilator action, peripheral, 288 
vasomotor centres, action on, 60, 61, 

62 
vessels, action on, 276 
Cholagogues, 170 
Cholesterin, distoxication of saponin 

and crotalus toxin, 569 
Choline, antagonism to atropine, 248 
to epinephrin, 164, 1SS, 189, 
568 
autonomic nervous system, action 

on, 142 
in ergot, 225 

gastric secretion, action of, on, 166 
heart, action on, 248 
miotic action of, 153 
motor nerve endings, action on. 9 
occurrence, L' IS 
pancreatic secretion, action of, on, 

168 
reproductive organs, action on, 21S 
salivary secret ion, action on, 16 I 
stomach movements, action of, on, 
187 
Chorea, arsenic in, 412 
Chkysahobix, ois 
Chrysotoxin, 226 

Ckmtoxin, action on vagus and vaso- 
motor centres, 'J 15 
Ciliary muscle, pharmacology of, I 15- 

I.V.l 

< 'INCHON A (See (Quinine) 

( !lNCHON18M, 477 



590 



INDEX 



Circulation, 231-331 

accelerator centres, drugs acting on, 
245, 246 
nerves, peripheral, drugs acting 
on, 252 
activity, effect of, 231 
blood-pressure determination, clin- 
ical, 236. 237 
capillaries, drugs acting on, 288 
capillary dilators, 288, 289 
cardiac and vascular depression, 

treatment of, 307 ff. 
compensating mechanism of, 231 ff. 
extra-systoles, 267, 268 
factors controlling, 231-234 
failure, treatment of, 307 ff. 
heart, bathmotropic function, 244 
calcium's importance for, 269 
accelerator centres and endings, 
influence of drugs acting on, 
245, 246, 252 
chronotropic function, 244 
automatism of, 253 
depressants of, 252-254 
disturbances of function of, 

290 
dromotropic function, 244 
fibrillation of, 256, 257 
inhibitory nerves, drugs acting 

on, 248 ff. 
inotropic function, 244 
motor centres, identity with 

accelerator endings, 252 
nerves, drugs acting on, 245 ff. 
nutrient solutions for, 269, 270 
pharmacology, 244 ff. 
physiology of, 244, 245 
rate, influence of drugs affecting 

blood-pressure, 245 
rate, inhibitory centre and end- 
ings, influence of drugs acting 
on, 245, 246 
stimulating, drugs, 255 ff. 
vagus depressants, peripheral, 

246 ff. 
vagus centres, drugs acting on, 
245 
methods of investigation of, 234- 
243 
of cardiac actions of drugs, 238- 
241 
frog's heart, 239 _ 
isolated mammalian heart 
(Hering - Bock), 240; 
(Langendorff), 241 
methods of investigation of, clinical, 
235-237 
experimental, 237, 238 
of vasomotor actions, 241-243 
on excised arteries, 241, 242 
by perfusion, 241, 242 
by plethysmogram, 242, 243 
by venous outflow, 242 
pharmacology of, 231-331 



Circulation, portal, reciprocal balance 
between systemic and, 232 
premature contractions (see Extra- 
systoles) 
pulmonary vessels, digitalis's effect 

on blood-pressure in, 266 
reciprocal action between heart and 

vessels, 233 
splanchnic nerve, importance of, 272 
toxines, action on, 309 
vascular crises, treatment of, 323 
depression, treatment of, 311 
poisons, 483 
vaso-constriction, treatment of, 

323 ff. 
vasoconstrictor (see also Vessels and 
Vasomotor) 
drugs, central, 273-276 
peripheral, 278-288 
central, 276 
vasodilator drugs, peripheral, 288 
vasodilatation, renal, hydraemia as 
cause of, 359 
substances causing, 358, 
359 
vasodilators (see Vessels and Vaso- 
motor) 
vasomotor effects of local applica- 
tions, 289, 290 
vessels, coronary, amyl nitrite, 289 
caffeine, 289, 313, 330 
renal, drugs acting on, 358, 359 

digitalis, action on, 365 
intracranial, action of caffeine 

on, 330 
pharmacology of, 270-290 
as a whole, effects produced by 
drugs acting on, 290 ff. 
Citrates, cathartic action of, 203 

coagulability of blood, action on, 448 
Climate, metabolism, effect on, 379 
Coal gas (see Carbon monoxide) 
Cocaine, accelerators, peripheral, action 
on, 252 
anaesthesia of eye by, 128 
antagonism to chloral, 25 
central nervous system, action on, 

26, 125 
cerebral stimulant and depressant, 

26 
constitution, 121, 131 
convulsant action of, 24 
distoxication of, 127 
elective action on sensory fibres, 

123-124 
endermic injection of, 128 
eye, action and uses in the, 158 
gastric secretion, action of, on, 167 
general pharmacological action, 

122 ff. 
history, 121, 122 
in infiltration anaesthesia, 128 
intra-ocular tension, effect on, 158 
metabolism, action on, 382 



INDEX 



591 



Cocaine, nerve blocking by, 123 

nerves of special sense, action on, 123 

poisoning by, 126 

treatment of, 126 

principles governing administration, 
127 

pyrogenic action of, 462, 473 

respiration, stimulating actionon, 335 

sensory nerve-endings, action on, 122 

special senses, action on, 123 

spinal anaesthesia by, 129 

substitutes for, 131 ff. 

comparative value of, 133 ff. 

swallowing reflex, action on, 176 

synergism between epinephrin and, 
159, 575 

systemic action, 125 

therapeutic employment of, 125 

toxicology, 126 

vessels, action on, 124 

in vomiting, 185 
Codeine chemistky, 31 

cough, in treatment of, 38 

morphine, differences from, 38 

respiratory centre, action on, 340 
Cod-liver oil, 174 
Cold, antiphlogistic action of, 492 

heat-regulating mechanism, action 
on, 453-455 

vessels, influence on, 453, 454 
Colic, intestinal mechanism of, 194 
Collapse, antipyretics as cause of, 466 

atropine in, 25 

camphor in, 25 

cocaine in, 25 
Colloids, obstipant action of, 211 

and salts, 570 
Coloctnth, 192, 206 
Concentration in blood, 562 
Condiments, stomach absorption, effect 
on, 173 

secretion, action of, on, 167 
Constipation, drugs causing (see Ob- 

stipants) 
Convallamarin, 302 
Convulsants, 23 

temperature, action on, 462, 473 
Copaiba, 367, 486 
Copper, elimination in bile, 170 
by intestine, 172 

muscular paralysis from, 427 

salts, in inflammation, 494 

sulphate, omotic action of, 182 

phosphorus, antidotef or, 1S3, 40S 

toxicity, lack of, 182 
Coriamyrtin, action on central nervous 
system, 24 

CORNUTINE, 226 

Corrosives, eye action in, 160. (See 
also Caustics) 

Coronary (see under Circulation, ves- 
sels, coronary) 

Cotarnine, uterus action on, 229 

Coto, diarrhoea in, 215 



Cough, morphine group in, 339, 340 

COUNTERIRRITANTS, 486 ff. 

leucocytes, action on, 447 

respiration, action on, 341 
Counterirritation, explanation of ef- 
fects, 484 
Creolin, 517 
Creosote compounds, 526 

in tuberculosis, 525-527 
Cresols, action on liver, 517 

as disinfectants, 516, 517 

relative toxicity of, 517 
Croton oil (see Oleum crotonis) 
Cubebs, 367, 486 
Cumulation, 563 
Curare, 1 ff». 

absorption, 5 

antagonism between phvsostigmine 
and, 9, 152, 572 

central nervous system, action on, 4 

circulation, action on, 4 

excretion, 5 

frog, action on, 2 

glycosuria, 5 

heart, action on, 247 

immunity of salamanders to, 573 

intestine, action on, 4 

mammals, action in, 4 

motor nerve-endings, action on, 1 

in strychnine poisoning, 19 

rigor of muscles, influence on, 424 

substances resembling, 8 

therapeutic use, 7 
Curarines, 2 
Curine, 2 
Cyanide poisoning, 450, 569 

distoxication of, 569 
Cytotoxins, 560 

Deglutition, as affected by drugs, 176 
Dermatol, 216 

Diabetes insipidus, drugs used in 
treatment, 366 

mellitus, 418 
Diabetic coma, alkalies in, 392 
Diaphoresis, 371-375 

indications for, 375 

in renal disease, 375 
Diaphoretics, central, 372, 373 

peripheral, 372 
Diarrhcea, drugs checking (sec Obsti- 

pants) 
Diethyl barbituric acid (see Veronal) 
Digalen, 301, 306 

DlGIPURATUM, 306 
DlGITALEIN, 301 
DlGITALIN, 301, 304 

Digitalis, active principles, 301 

blood-pressure increase from, 292 
bodies, differences in actions of, 302 
relative cumulative properties 

of different, 303, 304 
vaso-constrieting power, differ- 
ences in their, 288 



592 



INDEX 



Digitalis, cardiac failure, action in, 310 
circulator}' collapse, effects in, 323 
cumulative effects, 303 
deterioration of, 302 
distribution of the blood, effects on, 

296 
diuretic action of, 365 ff . 
dosage and choice of preparation, 

304, 305 
extra-systoles, power of causing, 267 
heart, action on, 261-267 

conductivity, action on, 266, 
267 . 
disease, effects in, 296 ff . 

frog's, action on, 262-264 

isolated mammalian, action on, 264, 

265 

toxic doses, effect on, 266 

work, effect on, 293, 294 

infusions, rapid deterioration of, 

302, 305 
intestinal motor function, action on, 

188, 191 
intravenous administration, 306 
kidney vessels, effect on, 287, 299 
physiological assay, methods, 301 
practical employment of, 301 ff. 
preparations, variability of, 301 
pulse retardation, 292 
pulse volume of heart, effect on, 293 
regulatory action of, 266, 294 
retardation of pulse by, 292 
stomach and intestinal movements, 

action on, 188 
summary of actions, 300 
theory of action of, 291 
toxic action of, 294 
vagus, action on, 245, 266, 292 
vasoconstriction under clinical con- 
ditions, 298 ff . 
vessels, renal, action on, 287, 299 
of different organs, quantita- 
tively different action on, 
286, 287 
peripheral action on, 286-288 
vomiting due to, 304, 306 

DlGITONINS, 301 
DlGITOXIN, 301 

importance of size of dose, 564 
Dimethylxanthines, action in kidney, 

289 
Dionin, 38 

in cough, 340 

eye, action in, 161 

respiration, action on, 340 

DlOXYDIAMIDOARSENOBENZOL (see Sal- 

varsan) 
Diphtheria, 553 ff. 
antitoxin, 556-558 
toxin, 555, 556 

action on vessels, 4S3 
on heart, 309 

DlPROPYLBARBITTJRIC ACID (see PropO- 

nal) 



Direct action, 6 

Disinfectants (see also Antiseptics) 

specific, 523 ff . 

in vitro and in corpore, 525 
Disinfection of instruments, etc., 508 

mucous membranes, 508, 509 

skin, 507 

wounds, 508, 509 
Distoxication, 569 

augmentation of power of, 574 
Distribution, 562 

factors affecting, 562 
Diuresis, ascites, effect of relief of, 357 

blood flow in kidney as factor in, 
357 ff. 

blood letting, effect on, 354 

caffeine group, action on, 360 

cardiac stasis, effect on, 357 

digitalis group, action on, 365 

factors controlling, 354 

hydrajmia, effect on, 354 

reflex inhibition of, 358 

saline infusions, effect on, 354 

sugars, action on, 356 

tubules, function of, factors influ- 
encing, 366 

vasoconstriction, renal, effect on, 
358 

urea as stimulant to, 356 

vasodilatation, renal, effect on, 359 
Dormiol, 93 
Drastic purgatives, 207 

abortifacient action of, 223, 224 
Duboisine, pancreatic secretion, action 
of, on, 168 

Ecgonine, 132, 133, 154 

Echuyin 302 

Ehrlich s side-chain theory, 550 ff . 

Elective action, 5 

Elimination of drugs in milk, 220 
rapidity of, 562 

Emesis, 181-1S5_ 

drugs sometimes causing, 185 
treatment of, 185 

Emetic centre, depressants of, 178 

Emetics, centrally acting, 179, 180 
expectorant action of, 179, 343 
peripheral, 181-185 

Emetine, 181, 182 

Emodin, 207 

Enemata, 194 

Enzymes, as caustics, 492 

Ephedrine and pseudo-ephedrine, 159 

Epinephrin, 279-285 

accelerator, peripheral, action on, 

252 
analeptic action of, 321, 322 
anaesthesia, local, use in, 2S0 
antiphlogistic action of, 496 
arteriosclerosis, a cause of, 282 
asthma, action in, 346 
blood-pressure, effects on, 281 
in chloroform death, 65, 320 



INDEX 



593 



Epinephein, circulatory failure, in treat- 
ment of, 320 ff . 
coagulability of blood, action on, 448 
constitution, 279 
coronary vessel, action on, 280 
diuresis, action on, 358 
elimination, 282 

evanescence of action, cause of, 282 
eye, action in, 159, 282 
fibrillation of heart, a cause of, 

322 
glycosuria, 282, 419 
in haemorrhage, 321 
haemostatic action of, 280 
heart, action on, 260, 261 
in heart failure, 320, 321 
hepatic function, action on, 171 
hypertension, a cause of, 323 ff . 
intestinal motor function, action on, 

191 
intravenous use of, 321 
kidney, action on vessels of, 280 
and pancreas hormone, 568 
pulmonary vessels, action on, 280 
pyrogenic action of, 462, 463 
reaction in pancreatic disease, 159 
respiration action on, 282 
salivary glands, effect on, 164, 282 
seat of action, 282 
significance (physiological), for the 

blood-pressure, 284 
in shock, 321 
spinal anaesthesia, in collapse from, 

321 
stomach movements, action on, 188 
subcutaneous injections, effects of, 

322 
sweat glands, lack of action on, 372 
and the sympathetic nerve-endings, 

141 
synergism between cocaine and, 159, 

160, 575 
tests for, physiological, 283 
uterine movements, action on, 222, 

223, 229 
vagus centre, effect on, 282 
vascular depression, in treatment of, 

320 ff. 
vasomotor paradox, 226 
vessels, action on, 279-283 
vascular paresis, in treatment of, 

320 ff. 
Epsom salt (see Magnesium sulphate, 

also Cathartics, saline) 
Erection, 219 
Ergot, 224-228 

active principles of, 225-227 

instability of, 227 
cock's comb, action on, 226 
in hemorrhage from uterus, 228 
physiological assay of, 227 
preparations of, 228 
therapeutic uses of, 228 
vasoconstrictor action of, 228 



Ergotin, stomach and intestinal move- 
ments, action on, 188 
Ergotism, 224, 225 
Ergotoxin, 225, 226, 227 

circulation, action on, 226 
sympathetic nerve-endings, action 
on, 142 
Erythrol tetranitrate, 329 
Erythrophlein, 302 
Escharotics, 491 ff. 
Eserine (see Physostigmine) 
Ether, 49-55 

Ether anaesthesia, after effects, 73, 74 
blood-pressure, effects on, 62 
asthma, action in, 345 
blood cells, action on, 56 
chemistry of, 53 
circulation, action on, 60 ff . 
circulatory failure, in treatment of, 

317 
concentration in air inspired, 72, 73 
in blood during anaesthesia, 70, 7 1 
excretion, 55 
general action, 54 

heart, stimulating action on, 257, 258 
local action, 54 

anaesthetic action, 54, 56 
respiration, action on, 59, 335 
a respiratory stimulant, 335 
synergism, 79, 576 
vasomotor centres, action on, 62 
vessels, action on, 275 
Ethereal oils, abortifacient action of, 
224 
antiphlogistic action of, 496 
carminative action, 211 
diuretic action of, 359 
gastric secretion, action on, 167 
kidney secretion, action, 359 
Ethyl bromide anaesthesia, 83 

chloride, local anaesthesia by, 118 
Etiotropic pharmacological agents, 

497 ff. 
Eucaine, 133 
B, 133 

relative toxicity of, 134 
action on vessels, 135 
Eumydrine, mydriatic action, 157 
Euonymin, 206, 302 
Euphthalmine, mydriatic action, 157 
Euquinine, 476 
Europhen, 520 

Excitability, exaltation of, 44 
Expectorants, 342 ff. 
mode of action, 342 
nauseant, 343 

effect on alveolar air, 339 
Eye, antiseptics in, 160 
astringents in, 160 
corrosives in, 160 
pharmacology of the, 144 ff. 

Felix mar, 521 

causing toxic amblyopia, 144 



594 



INDEX 



Fennel, carminative action, 211 

Ferratin, 442 

Fever, mechanism of, 459-463 

puncture hyperthermia, 460, 461 - 

significance of, 473-475 

substances causing, 462 
Fibrolysin, 489 
Filicic acid, 522 
Filicin, 522 
Formaldehyde, astringent action, 493 

as disinfectant, 507 
Frangttla, 208 
Functional condition of organs, 566 

Gall-bladder, atropine, action on, 169 

pilocarpine, action on, 169 
Gamboge, 206 

Gastric hypersecretion, inhibition of, 
167 
motility (see Stomach, motor func- 
tion of) 
secretion, 165-167 

acids, action of, on, 165 
albuminoses, action of, on, 165 
alkalies, action of, on, 165 
atropine, action of, on, 166 
bismuth, action of, on, 167 
bread, action of, on, 165 
choline, action of, on, 166 
cocaine, action of, on, 167 
condiments, action of, on, 167 
fats, action of, on, 165 
lime water, action of, on, 167 
local anaesthetics, action of, on, 

167 
magnesia, action of, on, 167 
meat extractives, action of, on, 

165 
morphine, action of, on, 166 
protectives, action of, on, 167 
Gelatine, coagulability of blood, action 

on, 448 
Genital glands, metabolism, influence 

on, 398 
Glauber's salt (see Sodium sulphate, 

also Cathartics, saline) 
Glaucoma, effect of atropine in, 155 
of cocaine in, 158 
of physostigmine in, 150 
Glottis, drugs acting on spasm of, 345 
Glycerine, intestine, action on, 194 
Glycosuria, asphyxial, agents causing, 
418 
drugs causing, 418, 419 
phloridzin, 419 
renal, drugs causing, 419 
suprarenal, 419 

thyroid substances, causing, 397 
Glycosurias, toxic, 418 
Glucuronic acid, 420 
Gout, atophan in, 421 

alkalies in, 390, 391 
Guaiacol, 526 

compounds, 526, 527 



Hemolytic toxins, 452, 559 
Haemolysis, 451 ff., 559 

as measure of intensity of pharma- 
cological action, 564 
Halogen salts, elimination by intes- 
tines, 172 
Hashisch, 41 

Headaches, antipyretics in, 475 
Heart (see under Circulation) 
Heat, heat-regulating mechanism, action 
on, 455, 456 
action on vessels, 290 
regulating centres, abnormal func- 
tion in fever, 459, 460, 461 
cooling a stimulant to, 457 
depression of, 458 
location of, 458 

overheating a depressant of, 458 
stimulation of, 457 
regulation, pharmacology of, 453- 
480 
physiology of, 453-458 
Hedonal, 95 
Helleborein, 302 
Helmitol, 367 
Heroin, respiration, action on, 38, 340 

HEXABROM - DIOXY - DIPHENYLCARBINOL, 

525 
Hexamethylenamine, elimination by 
bile, 170 
salivary glands, 165 
as urinary disinfectant, 367 
Hidrotics (see Diaphoretics) 
Hippol, 367 
Hirudin, 448 
His, bundle of, digitalis's action on, 266, 

267, 295 
Homatropine, mydriatic action, 157 
Homoeopathy, 561 
Hydr.emia, effect on diuresis, 354 

produced by salts, 354, 355 
Hydrastin, blood-vessels, action on, 229 

uterus, action on, 229 
Hydrastinine, blood-vessels, action on, 
229 
uterus, action on, 229 
Hydrastis, uterus, action on, 229 
Hydrocarbon narcotics, 43 ff. (See 

also Alcohol-chloroform group) 
Hydrogen peroxide as disinfectant, 511 
Hydrogen sulphide (see Sulphuretted 

hydrogen) 
Hyoscine (see Scopolamine) 
Hyoscy amine, d- and b-, 154 
Hyperemia, passive, explanation of 

effects, 485 
Hypersusceptibility, 577 
cellular, to toxins, 578 
due to peculiar composition of body 

fluids, 578 
from abnormal tone of nerves, 577 
from lime poverty, 577 
Hypnotics, absorption and elimination, 
importance of rate of, 84 



INDEX 



595 



Hypnotics of alcohol group, 84 ff. 
general action, 84 
side actions, 85 
of aliphatic series, heart, 'depressant 

action on, 252, 253 
chemical constitution and pharma- 
cological action, 98 ff. 
depth of sleep, effects on, 86, 87 
halogen-free compared with .halo- 
gen-containing, 93 
influence of halogen groups in, 99 
motor function, varying action on, 
of different, 87 
Hypophysis extracts, uterine contrac- 
tions, action on, 223, 230 
metabolism, influence on, 398 
Hyposulphites, in nitril posioning, 569 
Hypothyroidism, 396 

Ichthyol, 518 

Idiosyncrasy, 578. (See also Hyper- 
susceptibility, 578, and Anaphylaxis, 
580) 
Immunity, 573 

active and passive, 544 
cellular, 573 
Indirect action, 6 
Infiltration anaesthesia (see under 

Cocaine) 
Inflammation, excitation of, 481-492 
influence of caustics on, 483, 484 
of irritants and counterirri- 

tants on, 482 
of necrotizing agents on, 483, 

484 
of nerves on, 481, 482 
of vascular poisons on, 483 
inhibition of, 492-496. (See also 

Antiphlogistic agents, etc.) 
nature of, 481 
pharmacology of, 481-496 
Infusions, blood, in circulatory failure, 
318 
effect on concentration of blood, 

437 
in carbon monoxide poisoning, 

450 
saline, blood regeneration, in- 
fluence on, 435 
blood volume, effect on, 435 
circulatory failure, in treat- 
ment of, 318 
haemorrhage, value in, 319 
toxaemias, value in, 319 
Inhalations, action on lungs, 341 

antiseptic, 341 
Inhibition, removal of, 44 
Insomnia, causes, 85 
Insusceptibility, 573, 574 
to cantharidin, 574 
to emetics, 574 
of morphinist to cocaine, 574 
of mice to CO, 574 
of young animals to strychnine, 574 



Internal secretions, metabolism, in- 
fluence on, 398 
Intestinal disinfection, 201, 204, 520 

juice, secretion of, 171, 172 
Intestine, absorption in, 173 

large, cathartics acting on, 207 ff. 

motor function, 190 ff. 

small, cathartics acting on, 205 ff. 
elimination by, 172 
Iodides (see also Iodine) 

in asthma, 347 

in atheroma, 402 

elimination by saliva, 164 

expectorant action of, 343 

in metallic poisoning, 402 

in neuralgia, 402 

in syphilis, 401 

viscosity of blood action on, 448 
Iodine compounds (see also Iodine and 
Iodides) 

as counterirritant, 488 

ion action of, 399 

local action, 398, 488 

metabolism, action on, 398-402 

mucous membranes, action on, 400 

nutrition, action on, 400 

poisoning from, 488 

scrofula, action in, 401 

skin, action on, 400 

systemic actions, 399-402 

theory of, action of, 400, 401 

thyroid gland, action on, 400 
Iodipin, 402 
Iodoform, 518, 519 

toxicology, 519 

idiosyncrasy to, 580 

substitutes for, 519, 520 
Iodol, 520 

Iodothyrin, 395. (See also Thyroid 
substances) 

hepatic functions, action of, on, 171 
Ipecac, 181, 182 

in dysentery, 181, 182 

emetic action of, 181 

expectorant action, 343 
Iris, pharmacology of, 145-159 
Iron, alimentary canal, behavior in, 442 

blood, actions on, 435-443 

comparative value of different prep- 
arations of, 442 

content of foods, 441 

excretion of, 172, 438 

in food stuffs, 441 

inorganic, absorption of, 439 
effect on iron balance, 438 
preparations, 442 
relative superiority, 440 ff. 

transformation in(oh;einoglobin,439 

kidney, lack of action on, 443 

metabolism, action on, 415 

non-(o\ie by mouth, •>:'.'.) 

organic preparations, 442 

relative inferiority, 440 
transformation into haemoglobin, 440 



596 



INDEX 



Iron salts in inflammation, 494 
sulphate, as deodorant, 507 
tonic effect, 441 
toxicology, 442, 443 

Irritants, phlogistic effects of, 482 

Isoform, 520 

Isopral, 93 

Isovalerylurea, halogen compounds, 
100 

Itrol, 513 

Jaborandi, 373 
Jalap, 206 

Jambul in diabetes, 418 
Juniper, oil of, 486 

Juniperus sabinus, abortifacient action 
of, 224 

Kairine, 477 

Kalahari arrow poison, 483 

Kamala, 523 

Kidney, blood flow in, estimation of, 358 

vessels, digitalis action on, 365 
Kino, 214 
Koosso, 522 
Kousso, 522 
Koussotoxin, 522 
Krameria, 214 

Lactagogues, 220 
Lead acetate, absorbability of, 216 
astringent action of, 216 
elimination in bile, 170 
by intestine, 172 
in saliva, 165 
muscular paralysis from, 427 
organic compounds, toxicity of, 533 
salts, in inflammation, 494 
vascular crises, a cause of, 325 
Lecithin, metabolism, effect on, 417 
Leucocytes, drugs influencing, 446, 447 
Lime (see also Calcium) 

coagulability of blood, action on, 447 
as disinfectant, 506 
water, alimentary canal, action in, 
217 
gastric secretion, action of, on, 
167 
Liver, functions of, and epinephrin, 171 
and iodothyrin, 171 
and pancreatic internal secre- 
tion, 171 
Lobeline, asthma, action in, 345 
emetic action, 180 
respiration, stimulating action on, 
335 
Local anaesthetics, gastric secretion, 
action of, on, 167. (See also under 
Cocaine) 
Loretin, 520 
Losophan, 520 
Lysidin, 421 
Lysol, 517 



Magnesia, antidote for arsenic, 202 
calcined, 202 

gastric secretion, action of, on, 167 
usta (see Magnesia) 
Magnesium, anaesthetic action of, 110 
central nervous system, action on, 

110 
toxic action, 202 
sulphate, 201 
Mammary gland, influenced by other 
organs, 220 
secretion, elimination of drugs in, 
220 
Manganese, blood, action on, 443 
Mannite, 203 

Massage, metabolism, effect on, 379 
Meat extractives, gastric secretion, 

action of, on, 165 
Menthol, elimination in bile, 170 
Mercuric salts, antiseptic power in- 
fluenced by dissociability of, 
501-503 
differences in antiseptic powers, 
501-503 
Mercurial amalgam in inhalation 

curves, 541 
Mercury, bichloride of, as injection, 
541, 542 
intravenous injections, 542 
blood, action on, 415 
diuretic action of, 356 
double salts of, 502, 503 
elimination in bile, 170 
curves, 540-542 
by intestine, 172 
in saliva, 165 
inhalations, 541 
injections, insoluble, 542 

soluble, 541, 542 
intestine, toxic action on, 513 
inunctions, 541, 542 
kidney, action on, 542 
metabolism, action on, 415 
organic compounds for injections, 

542 
organic compounds, toxicity of, 533 
poisoning, acute, 415, 416, 513 
chronic, 415, 416 
subacute, 513 
oral administration, 541 
salicylate of, as injection, 542 
salts, as disinfectants, 512 
in syphilis, 539-543 
thymol-actetate of, as injection, 542 
yellow iodide in syphilis, 541 
Metabolism, alkalies, action on, 389 
arsenic, action on, 409 
carbohydrate, pharmacology of, 

418 ff. 
in diabetes, drugs affecting, 418 
dehydration, action on, 387 
in fever, 459, 460 

functional activity, influence of, 381 
iodides, influence of, 398 



INDEX 



597 



Metabolism, light, action on, 382 
mineral, 418 

osmotic changes, action on, 384, 385 
pharmacology of, 377 
phosphorus, 405 
physiology of, 377-381 
q uinin e, influence on, 403 
of purines, 421 
special phases of, 417 ff . 
stimulation of, 378-380 
temperature of body, influence on, 

382 
thyroid substances, influence on, 395 
water ingestion, action on, 384-386 
Metallic salts, antiseptic actions, 514, 
515 
astringent action, 215 ff. 
as caustics, 491 
Metblemoglobix, drugs causing forma- 
tion of, 451 
Methylatropine, 157 
Methyl chloride, local anaesthesia by, 
118 
ecgonine, 131 
Methylene blue, elimination in bile, 

170 
Migraine, nitrites in, 329 
Migrainine, 479 

Milk (see Mammary secretion, 220) 
Miosis due to arecoline, 153 
choline, 153 
muscarine, 153 
. nicotine, 153 

physostigmine, 148 ff. 
picrotoxine, 147 
pilocarpine, 153 
Miotics, centrally acting, 147 

peripheral, 147-153 
Mode of administration, 562 
Morphine, as analgesic, 36 

antagonism to atropine, 336 
antidotes for, 36 
antipyretic action, 465 
bladder, action of, on, 34 
as cerebral stimulant, 33 
chemistry of, 30, 31 
circulation, action of, on, 34 
compared with ether and chloro- 
form, 58 
constipating action of, 193 
constitution, 30 
convulsive action of, 32 
cough, effects on, 37, 339 
deglutition, effect on, 176 
a digitalis of the rcspirat ion, 339 
elimination by intestine, 36, 40, 172 
by saliva, 165 
by kidney, 40 
by stomach, 35 
emetic action, 34, 180 
euphoric action, 33 
fate in body, 40 
fo-tus, action on, 35, 575 
frog, action on, 31 



Morphine, gastric secretion, action of, 
on, 166 
habituation, causation of, 39, 574 
higher animals, action of, in, 32 
as hypnotic, 37 
insusceptibility acquired by cerebral 

cells, 574 
intestinal motor function, action on, 

192 
intestinal secretion, 193 
lethal dose, 34 
miotic action, 34, 147 
motor areas, action on, 32, 33 

reactions, action on, 33 
as narcotic, 29 
pain, action on, 32 
pancreatic secretion, action on, 16S 
poisoning, acute, 34 

acute treatment of, 35 
pupil, action on, 34, 147 
respiratory centre, action of, on, 33, 

337 ff. 
and scopolamine, 42, 79, 575 
scopolamine anaesthesia, 79 
source of, 30 

stomach absorption, effect on, 173 
movements, action on, 1S8, 1S9 
secretion, 166, 189 
synergism with ether or nitrous 

oxide, 575 
tetanic action of, 31, 32 
therapeutic uses, 36 
uterine contractions, action on, 223 
variability of effects in different 

animals, 32 
vessels, action on, 276 
Morphinism, 39 
Motor nerve endings, 1 ff. 

depression of, 1 ff. 
stimulation of, 9 ff. 
Mucilaginous substances, obstipant 

action of, 211 
Muscarine, antagonism to atropine, 
249, 250, 569, 571 
autonomic nervous system, action 

on, 142 
constitution, 248 
heart action on, 246-249 
miotic action of, 153 
poisoning, 251 

salivary secretion, action on, 164 
sweat glands, action on, 372, 373 
Muscles, anatomy and physiology, 422- 
424 
depressant drugs, 427 
involuntary (see Pharmacology of 

Vegetative System | 
ionic actions on, 422 
pharmacology of, 422-434 
red, function of, 423 
stimulants of, 428 ff. 
water content, influence of, 422- 

423 
white, function of, 423 



598 



INDEX 



Mushrooms, hemolysin in, 452 

poisoning, 251 
Musk, heart, action on, 257 
Mustard, oil of, 488 
Mydriatics, centrally acting, 147 

peripherally acting, 153 ff. 

Naphthalin, as intestinal antiseptic, 521 

in skin diseases, 518 
Narcosis (see also Anaesthesia, Hypnot- 
ics, etc.) 
theory of, 100 ff. 

distribution coefficients, 105, 106 

of narcotics in organism, 103 

elective absorption by nervous 

system, 102 
importance of lipoid solubility, 

101 
other types and causes of nar- 
cosis, 108 
side actions of narcotics, 107 
Narcotics of alcohol group, in vascular 
crises, 325, 326 
vasodilator action, peri- 
pheral, 288 
of alcohol-chloroform group (see 
Narcotics of Alcohol group, and 
Narcotics of Aliphatic series) 
metabolism, influence on, 382 
respiratory sedative action of, 337 
vessels, action on, 276 
Narcotine, 30, 37 
Nerve blocking, 117, 129 
Neuralgias, antipyretic group in, 475 
Neuronal, 97 
Nicotine (see also Tobacco) 

autonomic nervous system, action 

on, 140 ff. 
central actions, 373 
heart, action on, 246, 247 
intestinal motor function, action on, 

191 
miotic action of, 153 
stomach movements, action on, 187 
sweat glands, action on, 373 
uterine movements, action on, 222, 
223 
Nigelline, sweat glands, action on, 372 
Nirvanin, 132 

Nitrils, distoxication of, 569 
Nitrite poisoning, 216, 451, 569 
from saltpetre, 216 
from bismuth subnitrate, 216 
Nitrites (see also Amyl nitrite) 
in angina pectoris, 327-329 
asthma, use in, 346 
blood, action on, 451 
cerebral vessels, action on, 329 
coronary arteries, dilating action on, 

327 
various, differences between, 329 
in vasoconstriction, 327 
Nitrous oxide, anaesthesia, 80 ff. 

narcotic action, cause of, 108 



Nitrous oxide, oxygen anaesthesia, 81 
Nosophen, 520 
Novocaine, 132 

relative toxicity, 133, 134 

superiority of, 134, 135 

Obstipants, 211 ff. 

mode of action, 211 
Oils, ethereal, action on gastric secre- 
tion, 167 
on kidney, 359 
Oleates, biliary secretion, action on, 170 
Oleo-crotonic acid, 205 
Oleum crotonis, cathartic action of, 203 
Oleum morrhce, 174 

ricini, cathartic action of, 205 
Opium (see also Morphine) 

alkaloids other than morphine, 30,37 

composition of, 30, 37 

diabetes insipidus, in treatment of. 

366 
in diabetes mellitus, 418 
beating, 41 
therapeutic uses of, 37 
Orthoform, 132, 134 

new, 132 
Ovarian extract, artificial menopause, 

action on, 218 
Ovaries, choline, action on, 218 

uterus, etc., influence on develop- 
ment of, 218 
Ouabain, 302, 307 

Oxalates, coagulability of blood, action 
on, 448 
distoxication by calcium, 569 
intestine, action on, 175 
Oxaluria, 421 
Oxidation, substances inhibiting, 404 ff. 

OXYANTHRAQUINONE DERIVATIVES, 207 

Oxygen in carbon monoxide poisoning, 
450 
inhalations, 332, 333 
lack of, effect on respiration, 333 
tension, blood, influence on, 446 
metabolism, influence on, 404, 

405 
respiratory centres, influence 
on, 332 
Oxytoxics (see also Uterine contrac- 
tions, drugs influencing) 

Pancreas, internal secretion of, 169 

hepatic function, action on, 171 

Pancreatic secretion, 168, 169 

atropine, action of, on, 168 
choline, action of, on, 168 
duboisine, action of, on, 168 
morphine, action of, on, 168 
pilocarpine, action of, on, 168 

Pantopon, 37 

Papain, as caustic, 492 

Papaverine, 30 

Paraffin enemata, 194 

Parafuchsin, 536 



INDEX 



PaRAHYDRQXYPHENYLETHYLAMTNE, 226 

Paraldehyde, 87, 93 
Paramidophenol, 478 
Paranephrin (see Epinephrin) 
Parasympathetic nervous 6ystem (see 

Autonomic nervous system) 
Parathyroids, 396 
Pelletierine, 523 

toxic amblyopia from, 144 
Penetrating power, 561 
Pentamethylenediamine in ergot, 225 
Permanganate of potash (see Potas- 
sium permanganate) 
Peronin, 38, 161, 340 
eye action in, 161 
respiration, action on, 340 
Pharmacological action, factors and 
principles governing, 5 
nature of, 6 
reactions, factors affecting, 561 ff. 
Phenacetin (see Acetphenetidin) 
Phenol, antipyretic action of, 462, 473 
antiseptic actions, 514, 515 
gangrene from local application of, 

119 
glycuronic acid and, 420 
kidney, action on, 516 
local action, 515 

anaesthetic action of, 119 
poisoning, 515 

treatment of, 516 
urine, action on, 516 
Phenolpthalein, 208 
Phenoltetrachlorphthalein, 209 
Phenyl salicylate (see Salol) 
Phlogogenic agents, 483 ff. 
classification of, 484 
Phloridzin glycosuria, 366, 419 
Phosphorus, blood, action on, 406 
bone, action on, 406, 407 
metabolism, action on, 405-408 
poisoning, treatment of, 408 
therapeutic uses of, 408 
toxicology, 407 
Physostigmine accommodation, action 
on, 149 
antagonism between atropine and, 
152, 572 
curare and, 9, 152, 572 
autonomic nerve endings, 150 ff. 

nervous system, 142 
central actions, 152, 373 
glaucoma, action in, 150 
heart, action on, 152 

seat of action in, 251 
intestinal motor function, action on, 

190 
intra-ocular tension, action on, 149 
miotic action, 148 ff. 
motor nerve-endings, 9 
mucous glands, aft ion on, 151 
muscles, action on, 9, 151 
respiration, action on, 152 
salivary secretion, action on, 151, 164 



Physostigmine, stomach movements, 
action on, 187 
sweat secretion, action on, 372, 373 
uterine movements, action on, 222 
Phytotoxins, 547 

Picrotoxin, antipyretic action of, 462, 
473 
autonomic nervous centres, action 

on, 142 
convulsant action of, 23 
diaphoretic action, 372 
medulla, action on, 24 
vasoconstrictor and vagus centres, 
action on, 274 
Pilocarpine, absorbant effects of, 375 
antagonism to atropine in sweat 

glands, 373, 572 
biliary secretion, action on, 169 
bronchial glands, action on, 343 
central nervous system, action on, 

374 
collapse from, 374, 375 
diaphoretic actions, 373 
eye, action on, 153 
general actions, 374 
heart, action on, 247 
intestinal motor function, action on, 

190 
leucocytes, influence on, 447 
mammary secretion, action on, 220 
metabolism, action on, 374 
pancreatic secretion, action of, on, 

168 
salivary secretion, action on, 163 
stomach motor function, action on, 

187 
stomach secretion, action on, 166 
secretions, action on, 373, 374 
uterine movements, action on, 222, 
223 
Piperazine, 421 

Piperidin, "curare" action of, 8 
Pituitrin (see Hypophysis extracts) 
Pix liquida, in skin diseases, 518 
Placental extracts, lactagogue action, 

220 
Plumbi acetas (see Lead acetate) 
Podophyllin, 206 
Polycythemia, 446 
Potassium bitartrate, 202 
chlorate, as antiseptic, 511 
systemic effects, 512 
toxicology, 512 
heart, depressant ad ion on, 253 
iodide (see also Iodides and Iodine) 
mammary secretion, inhibitory 
action on, 220 
permanganate in morphine poison- 
ing, 36 
in phosphorus poisoning, 408 
as disinfectant and preserva- 
tive, 511 
salts, central nervous svst cm , action 
on, 111 



600 



INDEX 



Potassium salts, diuretic action, 356, 
359 

and sodium tartrate, 202 
Precipitins, 560 
Primary action, 6 
Primula toxin, 483 
Pro pon al, 97 
Protargol, 514 

Protective s, antiphlogistic effects of, 
493 

gastric secretion, action on, 167 
Ptramidon, 480 
Pyrazolon derivatives, 479 
Pyrogallol, as antiseptic, 517 

blood, action on, 451 
Pyrogenic substances, 462 

collapse action of, 466 



Quebracho bark, 180 

quercus alba, 214 

Quillaja bark, expectorant action, 344 

Quinine amblyopia, 144 

antiphlogistic action, 496 

antipyretic action of, 470, 471 

as bitter, 476 

constitution, 476 

elimination in saliva, 165 

enzymes, inhibitory action on, 403, 
471 

fate and excretion, 477 

fever, action in, 404 

heart, depressant action of, 253 

heat-regulating centres, action on, 
471 

leucocytes, action on, 447 

in malaria, 527-529 

metabolism, action on, 403, 404 
of proteid, action on, 403, 471 

muscles, action on, 403 

puncture hyperthermia, action in, 
471 

salts of, 476 

source, 475 

temperature, action on, 470, 471 

therapeutic uses, 476 

tonic action, 476 

toxic action, 477 

in typhoid, 471 

uterine contractions, action on, 223 
QuiNOLiNE, constitution, 477 



Rabies, vaccination against, 544, 545 
Radiant energy, metabolism, action on, 

383 
Radio-active waters, 383 
Radium, metabolism, action on, 383 
Rectum, absorption in, 174 
of poisons by, 174 
Remote action, 6 
Renal antiseptics, 364 

function (see Diuresis and Renal 
Secretion) 



Renal function, pharmacology of, 
348 ff. 

physiology of, 348-354 
secretion, blood flow, influence on, 
350 
glomeruli, role played by, 350 
impaired permeability of glom- 
eruli, influence on, 351 
sodium chloride group, influ- 
ence on, 350 
theory of, 349 ff . 
tubules, role played in, 351, 352 
vasodilators, 360 ff . 
Reproductive organs, pharmacology 

of, 218 
Resinous acids, cathartic, 206 
Resorcin, as antiseptic, 517 
Respiration, counterirritants, action on, 
341 
pharmacology of, 332 
sedatives (central) of, 337-340 
stimulants (central) of, 334 ff . 
Respiratory centres, reflex stimula- 
tion of, 336 
Retina, pharmacology of the, 144, 145 
action of carbonic acid on, 144 
of chloroform on, 144 
strychnine on, 145 
santonin on, 145 
augmentors of excitability of, 145 
hyperaesthesia of, drugs' relieving, 
144 
Rhamnus purshiana (see Cascara) 
Rhatany, 214 
Rheum (see Rhubarb) 
Rhubarb, 208 

Rhus toxicodendron, phlogogenic ac- 
tion, 483 
Ringer's solution, 388 
Rontgen rays (see X-rays) 
Rottlerin, 523 
Rubefacients, 482, 483 



Sabromin, 115 
Sacral anaesthesia, 120 
Sajodin, 402 

Salicylates, antipyretic action of, 472 
bile, action on, 170 
blood, action on, 451 
carbon dioxide's influence on, 530 
in diabetes, 366, 418 
diaphoretic action, 374 
kidney, action on, 531 
leucocytes, action on, 447 
metabolism of proteid, action on, 

472 
uric acid metabolism, action on, 
421 
Salicylic acid, antiseptic action, 518 
group of antipyretics, 480 
as intestinal antiseptic, 521 
in rheumatism, 529-531 
uterus, action on, 224 



INDEX 



601 



Salicylism, 480, 530, 531 
Saline infusions (see Infusions, saline) 
Salipyrine, 479 

Salivary glands, elimination by, 165. 
(See Salivary secretion) 
secretion, pharmacology of, 162-165 
acids, action on, 163 
atropine, action on, 164 
bitters, action on, 163 
choline, action on, 164 
direct stimulation of, 163 
inhibition of, 164 
mercury, action on, 164 
muscarine, action on, 164 
physostigmine, action on, 164 
pilocarpine, action on, 164 
reflex stimulation of, 163 
tobacco, action on, 164 
Salol, as intestinal antiseptic, 521 

renal antiseptic action, 367 
Salt-poor diet, diuretic action of, 356 
Salts, acid, local action, 394 
diuretic action of, 355 
as diuretics, contraindications for, 

356 
neutral (see also Sodium chloride 
group) 
alkali loss produced by, 388 
metabolism, action on, 387 

of proteid, action on, 387, 
388 
skin, action on, 487 
stomach, effect on movements 
of, 187 
Salvarsan, 537 ff. 
constitution, 536 
employment in man, 537, 538 
elimination, 538 
in relapsing fever, 537 
in syphilis, 538 
Sandalwood, 367, 486 
Santonin, antipyretic, action of, 462, 473 
as anthelmintic, 523 
convulsant action of, 24 
toxicology, 523, 524 
Saponin, haemolysis by, 452 

pharmacological actions, 344 
Saprol, 517 
scammony, 206 

SCILLAIN, 302 

Sclererythrin, 225 
l-scopolamine, 154 
Scopolamine, chemistry of, 27 

eye, action in, 157 

as a hypnotic, 27, 28 

identity with hyoscine, 27 

motor centres, action of, on, 28 

mydriatic action, 157 

relation to atropine, 27 

synergism, with morphine, etc., 42, 
' 79, 82, 575 

toxic net ion, 28 

uterine contractions, action on, 223 

variability of preparations of, 29 



Scurvy, role of neutral salts in, 388 
Sea baths, metabolism, effect on, 379 
Sea-sickness, chloral, etc., in, 326 
Secalin toxin, 226 
Secondary action, 6 
Seignette salt, 202 
Senega, expectorant action, 344 
Senna, 207 

Sensory nerve-endings, pharmacology 
of, 117 
nerves, reflex effects of stimulation 
of, 117 
Sepsin, capillary dilating action of, 289 
Sequardine, 434 
Sera, bactericidal, 558 
Serum therapy, 546 ff . 
Side-chain theory, 550 
Silver nitrate, absorption of, 216 

astringent action in alimentary 

canal, 216 
in inflammation, 494 
organic compounds, 514 
salts as antispetics, 513, 514 
chemotactic pow 7 er, 513 
Sinigrin, 488 
Smelling salts, 336 
Snake venom, phlogogenic action, 4S3 

sera against, 551 
Soda (see Sodium bicarbonate) 
Sodium bicarbonate, biliary secretion, 
action on, 17.0 
gastric motility, action on, 186 
chloride, diuresis, action on, 355, 
356 
fever, 463 
group as expectorants, 343. 

(See also Salts, neutral) 
and vegetable diet, 449 
ions, action on muscles, 422 
nitrate, nitrite action of, 330 
phosphate, 202 

salicylate, therapeutic effects, 4S0 
sulphate, 201 

coagulability of blood, action 
on, 448 
Sozoiodol, 520 
sozoiodolic acid, 516 
Spanish fly (see Cantharidin) 
Sphacelic acid, 226 
Sphacelotoxin, 226 
Sphygmograms, 235 
Spinal analgesia, by cocaine, etc., 129 

by magnesium salts, 110 
Stasis, cardiac, 233 
Stimulation, significance of, 13, 14 
Stomach, absorption in, 172 
alcohol, effect on, 173 
bitters, effed on, 17:', 
carbonic acid, effect on, 173 
condiments, effed mi, 173 
colloids, effed on, 173 

motor function of, 186 189 

autonomic drugs, action 
on, 187 



602 



INDEX 



Stomach, secretory function of (see Gas- 
tric secretion) 
Stovaine, 133, 134, 135 
Strophanthin, 302, 304, 306, 307, 310 

in circulatory collapse, 323 

intravenous use, 306, 323 
Strophanthus (see Strophanthin) 
Strychnine, antidotal action of, 20 

brain and medulla, action of, on, 
17 

chemistry of, 13 

circulation, action of, on, 18 

"curare," action of, 19 

death, cause of, 19 

in diabetes insipidus, 366 

diaphonetic action, 372 

diuresis, action on, 358, 366 

excretion of, 21 

frog, action in, 13 

heart, action on tone of, 311 

higher animals, action on, 16 

intestinal motor function, action on, 
191 

kidney vessels, action on, 273 

metabolism, action on, 379 

muscular function, effect on, 424, 
427 

paralytic action of, 18 

poisoning, treatment of, 19 

respiration, action on, 18 

a respiratory stimulant, 335 

retina, action on, 145 

seat of action of, 14 

source of, 12 

special senses, action on, 18 

stomach tone, action on, 188 

test for, 13 

theory of action of, 15 

therapeutic uses, 20 

toxicology, 19 

vascular depression, in treatment of, 
311 

vagus centre, action on, 245 

vasomotor centres, action of, on, 18, 
273 
Stypticin, 229 
Styptol, 229 

StJBLAMINE, 513 

Succus entericus (see Intestinal juice, 

171) 
Sudorific (see Diaphoresis) 
Sugar, in muscular fatigue, 431 
Sulphates, in lead poisoning, 201 

in phenol poisoning, 201, 516 
Sulphides, alkaline, cathartic action of, 
209 
skin, action on, 487 
Sulphites, as preservatives, 510 
sulpho-carbolates, 516 
Sulphonal, 95, 96, 98 

blood, action on, 451 

group, 94 ff. 
Sulphonethylmethane (see Trional) 
Sulphonmethane (see Sulphonal) 



Sulphur, cathartic action of, 209 
skin, action on, 487 
toxic action of, 210 
Sulphuretted hydrogen, 210 

antidote in metallic poisoning, 

210 
bronchial mucous membrane, 

action on, 210 
local action, 210 
Suppurants, 489 ff . 
Suprarenal (see also Epinephrin) 
Suprarenals, metabolism, role in, 398 
Sweat (see Diaphoresis and Antisu- 
dorifics) 
physiology of, 369-371 
secretion of, 369-376 

astringents, action on, 376 
inhibition of, 375, 376 
Sympathetic nervous system, 136- 
141 
anatomy and physiology 

of, 137, 138 
antagonism between auto- 
nomic nervous system 
and, 140 
Synergism, 575 

of antiseptics, 576 
between cocaine and epinephrin, 159, 
575 
ether and chloroform, 79, 576 
magnesium sulphate and chlo- 
roform, 575 
morphine, scopolamine, and 

ether, 79 
morphine and scopolamine, 79, 
82, 575 
of opium alkaloids, 576 
of trypanosome remedies, 576 
Synergistic actions on temperature, 

473 
Syphilis, iodides in, 401 
mercury in, 539-543 
Systemic action, 5 



Tamarind, 203 
Tannalbin, 215 
Tannic acid (see Tannin) 
Tannigen, 215 
Tannin, 214 

absorption, 214 

action after, 214 
alimentary canal, action in, 214 
compounds of, 214 
dysentery action in, 182, 214 
Tannins, 213 
Tannocoll, 215 

Tansy, abortifacient action of, 224 
Tartar emetic (see Antimony and Po- 
tassium tartrate and antimony) 
Temperature of body, respiration, 
action on, 333 
drugs affecting, influence on metab- 
olism, 382 



INDEX 



603 



Testicles, influence on secondary sexual 

characteristics, 219 
Testicular extracts, muscles, influ- 
ence on, 433 
Tetanus, 552 ff. 
antitoxin, 554 
drugs causing, 13 
incubation period, 553 
toxin, mode of distribution, 553 
Tetrabrom-o-kresol, 525 
Tetraethyl-ammonium, 8 
.B-Tetrahydroxaphthylamixe, 159 
Tetrahydroxaphthylamixe, pyrogenic 

action of, 462 
Tetrametbylexediamtne in ergot, 225 

in ammonium, 8 
Tetronal, 95, 98 
Thallix, 477 
Thebaixe, 304 
Theixe (see Caffeine, 314) 
Theobromixe (see also Caffeine and C. 
group) 
accelerator, peripheral, action on, 

252 
in angina pectoris, 330 
constitution, 360 
digestive system, action on, 364 
diuretic action of, 364 
preparations of, 364 
in vascular crises, 331 
vessels, action on, 274, 289, 330 

dilator action on cerebral, cor- 
onary and renal, 289 
Theocix (see Theophylline) 
Theophylline, constitution, 360 
digestive system, action on, 364 
diuretic action, 364 
vessels, action on, 274. (See also 
Caffeine and Theobromine) 
Thiosixamixe, 489 
Threshold dose, 564 
Thuja occidextalis, abortifacient ac- 
tion of, 224 
Thymol, as antiseptic, 517 
anthelmintic, 524 
as intestinal antiseptic, 521 
poisoning from, 524 
in uncinariasis, 524 
Thyroglobulin, 395. (See also Thy- 
roid substances) 
Thyroid substances, estimation in 
blood, 397 
glycosuria, resulting from, 397 
in hypothyroidism, 396 
metabolism, influence on, 395- 

397 
in obesity, 396,397 
poisoning from, 397 
Thyroiodin, 395. (See also Thyroid 

substances) 
Tobacco (see also Nicotine) 
as abortifacient, 223 
amblyopia, 144 
poisoning, circulation in, 247 



Toxins, nature and properties, 546, 
547 

passage along nerves, 545, 553, 556 

vessels, action on, 276 
Toxoids, 550 

Transfusion (see Infusions) 
Triferrix, 442 
Trioxal, 95, 98 

Tropaic acid, constitution, 154 
Tropacocaixe, 131, 134 

action on vessels, 135 
Tropixe, constitution, 153 
Trypan red, 536 
Tryparosax, 536 
Trypsin, as caustic, 492 
Tuberculix, phlogogenic action, 4S3, 
490 

treatment, 546 
Turpextixe, 486 

action in lungs, 487 

in phosphorus poisoning, 408 



Urethan, 94 

in asthma, 345 
Uracil in ergot, 225 
Urea, diuretic action of, 356, 359 

renal secretion, influence on, 350 
Uric acid solvexts, 421 
Urinary axtiseptics, 367 
Urine, alkalies, action on, 368 

secretion of (see Renal secretion) 
Urotropixe (see Hexamethylenamine) 
Uterine movements, atropine, action 
on, 222 
drugs influencing — centrally or 

reflexly, 223, 224 
pharmacology of, 221 ff. 
pilocarpine, action on, 222 
Uterus, gravid and non-gravid, differ- 
ence in pharmacological reactions, 222 
Uva ursi, 367 



Vagus (see Circulation, Heart, Inhibi- 
tory nerve) 
Valerian, action on central nervous 
system, 115 
in diabetes insipidus, 366 
Validol, 115 
Valvyl, 115 

Vascular (see under Circulation) 
Vasomotor, etc. (see under Circula- 
tion) 
Vasotonin, 331 
Vegetative xervocs system, 136 ff. 

anatomy and physiology, 

136-188 
action of nicotine on, 140 
Veratrixe, antipyretic effects, 426, 466 
blood-pressure, action on, 427 
cardiac muscle, action on, 426 
circulation, action on, 427 
emetic, action on, 180 



604 INDEX 



¥** 



Veratrine, local action, 427 
muscles, action on, 425-427 
nerves, passage along, 425 

Veratrum (see Veratrine) 

Veronal, 97 

Vesicants, 489 ff. 

Vessels (see under Circulation) 



Water, absorption of, 386 
diuretic action of, 354 
lack of, metabolic effects, 387 
local action, 385, 386 
metabolism, action on, 386, 387 
pharmacological actions of, 385-387 



Xeroform, 520 

X-rays, leucocytes, action on, 447 

metabolism, action on, 383 

ovaries, effect on, 218 

testicles, effect on, 218 

Yew tree (see Thuja occidentalis) 
Yohimbin, aphrodisiac action, 219 

vessels, elective action on certain, 
289 

in vascular diseases, 331 



Zinc salts, in inflammation, 494 
Zinc sulphate, emetic action of, 183 



